Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.705 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
17.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 10 mg/kg/day from an OECD 408 oral study with rats on a read-across substance was used.  Assuming an oral/inhalation absorption of 1.0, a dose descriptor of 17.6 mg/m3 was derived as the starting point.

AF for dose response relationship:
1
Justification:
In accordance with ECHA guidance
AF for differences in duration of exposure:
2
Justification:
In accordance with ECHA guidance
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with ECHA guidance
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA guidance
AF for intraspecies differences:
5
Justification:
In accordance with ECHA guidance
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA guidance
AF for remaining uncertainties:
1
Justification:
In accordance with ECHA guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
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:
970.87 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
97 087 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 10 mg/kg/day from an OECD 408 oral study with rats on a read-across substance was used.  A dermal penetration study is available.  The mean penetrated  amount is 0.0103% of applied dose on human skin.  Therefore 10 mg/kg/day/0.000103 results in a dose descriptor of 97087 as the starting point.

AF for dose response relationship:
1
Justification:
In accordance with ECHA guidance
AF for differences in duration of exposure:
2
Justification:
In accordance with ECHA guidance
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with ECHA guidance
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA guidance
AF for intraspecies differences:
5
Justification:
In accordance with ECHA guidance
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA guidance
AF for remaining uncertainties:
1
Justification:
In accordance with ECHA 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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

CAS# 13472 -08 -7 DNEL Discussion Revised 4-17-2017

 

The DNELs for the registered substance were calculated using the results from an OECD 408 study conducted with the read-across substance, 2,2’-azodi(isobutyronitrile) CAS# 78-67-1.

 

In conclusion, daily administration of the read-across substance for 13 weeks at dose levels of 0.5, 2 or 10 mg/kg/day was well tolerated. There was no evidence of neurotoxicity. There were slight changes in some blood clinical chemistry and urine parameters at all dose levels. The liver and kidney were identified as target organs based on increased weights (at all dose levels in males) and

microscopic findings of hepatocyte hypertrophy (at all dose levels in males and at =2 mg/kg/day in females) and focal nephropathy/tubular basophilia and hyaline droplets in males at all dose

levels. The liver hypertrophy is considered an adaptive change commonly associated with metabolic burden and the changes in the kidney are considered specific to the male rat as

confirmed by immunohistochemical staining. Therefore, the nature of these histopathological changes are considered to be of no toxicological relevance and the No-Observed-Adverse-Effect-

Level (NOAEL) is considered to be 10 mg/kg/day.

 

Systemic Dermal DNEL Worker

A systemic NOAEL of 10 mg/kg/day is based on the OECD 408 oral rat gavage study.

 

Oral absorption rat — oral/dermal absorption human: A dermal penetration study is available. The mean penetrated amount is 0.0103%of applied dose on human skin. 

 

= 10 mg/kg bw/day/0.000103

= 97,087 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

= 97087 mg/kg bw/day / 10

= 9708.7 mg/kg bw/day

Correction for intraspecies differences: 5

= 9708.7 mg/kg bw/day / 5

= 1941.7 mg/kg bw/day

Correction for duration between 90 day exposure to chronic: 2

= 1941.7 mg/kg bw/day / 2

                       = 970.87 mg/kg bw/day

Correction for dose-response: 1

= 970.87 mg/kg bw/day / 1

= 970.87 mg/kg bw/day

Correction of whole database: 1 due to quality of study

= 970.87 mg/kg bw/day / 1

= 970.87 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.”

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

= 17.621 mg/m3inhalation dose descriptor

 

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

 

 

Additional correction for interspecies differences: 2.5

 

= 17.621 mg/m3/2.5

 = 7.048 mg/m3

 

Correction for intraspecies differences: 5

 

= 7.048 mg/m3/ 5

= 1.41 mg/m3

 

Correction for duration between 90 day exposure to chronic: 2

 

= 1.41 rng/m3/ 2

= 0.705 mg/m3

 

Correction for dose-response: 1

 = 0.705 mg/m3/ 1

= 0.705 mg/m3

Correction of whole database: 1 due to quality of study

 = 0.705 mg/m3/1

= 0.705 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:
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