Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
70.48 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):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
881 mg/m³
Explanation for the modification of the dose descriptor starting point:
Theroretical chronic systemic level
AF for dose response relationship:
1
Justification:
starting point is NOAEL
AF for differences in duration of exposure:
1
Justification:
chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not used for inhalation
AF for other interspecies differences:
2.5
Justification:
pharmacodynamic
AF for intraspecies differences:
5
Justification:
variability in workers
AF for the quality of the whole database:
1
Justification:
adequate
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 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):
50
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Dermal penetration is established for substances of similar structure; no major portal of entry effects; metabolites similar to those seen after oral administration
AF for dose response relationship:
1
Justification:
Dose response is seen in oral toxicity studies
AF for differences in duration of exposure:
1
Justification:
chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
remainder; pharmacodynamic
AF for intraspecies differences:
5
Justification:
individual variability
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The safety of the ester IPB is based on the opinions of authoritative bodies (EFSA, 2011, JECFA, 2001) and on the previously established safety of its metabolic products, benzoic acid and isopropyl alcohol. Benzoic acid esters are metabolised to benzoic acid and the corresponding alcohol inside the mammalian body when they encounter an acidic environment such as the stomach, or when they are metabolised by carboxyesterases, either in the gastrointestingal tract or intracellularly. The benzoic acid is conjugated with glycine and eliminated in the urine as hippuric acid (EFSA, 2011). The alcohols are metabolised to acids in the liver or intracellularly by alcohol dehydrogenase and aldehyde dehydrogenase. 

IPB is listed with JECFA as No. 855. Beginning in 1996, the benzoic acid derivatives were evaluated as a group/category, based on common metabolites. IPB is currently included in EFSA’s 2011 Table 3, Supporting Substances (FL 09-770) for benzyl derivatives, and was noted to have “No safety concern” as an added flavouring to food. 

Benzoic acid and its sodium and potassium salts are considered to be of low mammalian toxicity, and a reiteration of the significant body of existing toxicity studies (see EFSA, 2011 and 2005, SCF 2002, JECFA 1983 and 1996, WHO 2000, OECD SIDS 2001) is beyond the scope of this registration. Expert groups in these organizations added data from the 41 category members, including benzyl acetate, benzyl alcohol and benzaldehyde, relevant to the body of knowledge on benzoic acid (WHO, 2000). The SCF, 2002, recently reviewed genotoxicity and reproductive/developmental toxicity data on benzoic acid and its category members to satisfy data gaps, and concluded that no increased risks are evident for these endpoints.  Various benzoates are approved food additives, and are allowed in the diet at levels which do not exceed (as a group) 0-5 mg/kg bw/d in humans (JECFA 1983).  

The NOAEL from which the ADI is derived is obtained from Kieckebusch and Lang, 1960, who published a long term (4-generation) dietary toxicity study in rats at doses of 0.5% and 1%. The NOAEL is 1% in the diet or 10,000 ppm. Authoritative bodies have restated the doses in various ways: 250 and 500 mg/kg/d (JECFA 1983 and WHO, 2000), 275 and 550 mg/kg bw/d (EFSA 2011) and 375 and 750 mg/kg/d (OECD SIDS 2001). JECFA and EFSA determine this value to be 500 mg/kg bw/d. In support of this value, Kimmel et al., 1971, identified a dose of 510 mg/kg bw/d as the reproductive NOAEL for effects after exposure to a single gavage benzoic acid dose on gestational day 9; there was no specific developmental toxicity seen.  Therapeutic use of sodium benzoate at this level (approximately 250-500 mg/kg bw/d) in humans resulted in no significant toxicity (except occasional anorexia and vomiting) (WHO 2000). The parental NOAEL from several developmental toxicity studies in rats on orally administered isopropyl alcohol is comparable, 400 mg/kg bw/d (Tyl et al., 1994) and 500 mg/kg bw/d (Beyer, 1993). No developmental toxicity was observed.

The value of 500 mg/kg bw/d is established for the NOAEL from which DNELs are derived.

Concerning the finding that undiluted IPB may be a weak sensitiser, a recommendation for general risk management measures for workers, such a gloves, can appropriately mitigate this risk.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.24 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
Modified dose descriptor starting point:
NOAEC
Value:
881 mg/m³
Explanation for the modification of the dose descriptor starting point:
Theoretical chronic systemic level
AF for dose response relationship:
1
Justification:
starting point is NOAEL
AF for differences in duration of exposure:
1
Justification:
chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not used for inhalation
AF for other interspecies differences:
2.5
Justification:
pharmacodynamics
AF for intraspecies differences:
10
Justification:
Consumer
AF for the quality of the whole database:
1
Justification:
adeuate
AF for remaining uncertainties:
1
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:
DNEL (Derived No Effect Level)
Value:
5 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
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Dermal penetration is established for substances of similar structure; no major portal of entry effects; metabolites similar to those seen after oral administration
AF for dose response relationship:
1
Justification:
Dose response observed in oral tox studies
AF for differences in duration of exposure:
1
Justification:
chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
remainder, pharmacodynamic
AF for intraspecies differences:
10
Justification:
Consumers
AF for the quality of the whole database:
1
Justification:
adequate
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: JECFA, 1983 ADI of 0-5 mg/kg bw/d and EFSA, 2011 opinion of Flavour Group 20 "no concern".
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route-to-route performed
AF for dose response relationship:
1
Justification:
dose response observed
AF for differences in duration of exposure:
1
Justification:
chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
remainder; pharmacodynamic
AF for intraspecies differences:
10
Justification:
individual variability
AF for the quality of the whole database:
1
Justification:
full dataset available on category members
AF for remaining uncertainties:
1
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

IPB is listed with JECFA as No. 855 and in EFSA’s 2011 Table 3, Supporting Substances (FL 09-770) for benzyl derivatives, noted to have “No safety concern” as an added flavouring to food.  Various benzoates are approved food additives, and are allowed in the diet at levels which do not exceed (as a group) 0-5 mg/kg bw/d in humans (JECFA 1983). This is adopted from JECFA for consumer systemic chronic oral exposure. The calculations are identical to those for REACH DNELs: a NOAEL of 500 mg/kg bw/d (Kieckebusch and Lang, 1960) with a 100 -fold assessment factor.