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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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:
4.94 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
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
123.42 mg/m³
Explanation for the modification of the dose descriptor starting point:

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term inhalation DNEL by route-to-route extrapolation.


Dose descriptor starting point: NOAEL (OECD408, rat, gavage) = 100 mg/kg bw/d.


Modification: Ratio of oral to inhalation absoption: 0.5; standard respiratory volume, rat, corrected for 8 h exposure: 1/0.38 m3/kg bw; correction for activity driven differences of respiratory volumes in workers compared to workers at rest: 6.7 m3 / 10 m3, Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker.


 

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
Default for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
2.8 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
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
280 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No repeated dose dermal toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.


Dose descriptor starting point: NOAEL (OECD408, rat, gavage) = 100 mg/kg bw/d.


Modification: Ratio of oral to idermal absoption: 2; Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker.


 

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used (OECD TG study with 3 doses).
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
Default for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
135 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other: BASF position, 2009
Overall assessment factor (AF):
10
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General


DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).


Kinetics (absorption for oral, dermal and inhalation route of exposure)
No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed – in the absence of route-specific information on the starting route – to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. For dermal absorption, based on a weight of evidence approach, a ratio of 2:1 is used for oral-to-dermal extrapolation.


Acute toxicity
1,2-Dimethylimidazole has to be classified for acute oral toxicity (Cat. 4, H302). However, a short-term DNEL is deemed unnecessary because the long-term DNELs are considered to ensure sufficient protection to prevent peak exposure.


Repeated dose toxicity
In a GLP compliant 90-days repeated dose toxicity study, 1,2-dimethylimidazole was given to rats by oral gavage at dose levels of 0, 30, 100, or 300 (200) mg/kg bw/d. Treatment-related, adverse effects only were observed in the highest dose tested. Based on these results, a systemic NOAEL of 100 mg/kg bw/day was derived. In an developmental toxicity study.


In a pre-natal developmental toxicity study 1,2-dimethylimidazole was given to pregnant rats by oral gavage from GD6-19 at dose levels of 0, 120, 360 mg/kg bw/d. Maternal and developmental toxicity was observed in the high dose, and a NOAEL of 120 mg/kg bw/d was derived for maternal and developmental toxicity. The DNEL based on the oral 90d-study is considered to ensure sufficient protection to prevent reproductive toxicity. 


The NOAEL of the OECD TG 408 study was choosed for DNEL derivation, as this was the most meaningfull and the study was the most recent study conducted under GLP.  


Irritation / Sensitisation / Mutagenicity
1,2-dimethylimidazole is considered to be irritating to the skin (Cat. 2, H315) and causes serious damage to the eyes (Cat. 1, H318). Since only a qualitative assessment was made on the irritating potential of 1,2-dimethylimidazole to the skin, no local acute DNEL for dermal exposure could be derived.
1,2-dimethylimidazole is considered to be sensitizing to the skin (Cat. 1B, H317). In a LLNA in mice, proliferation in draining lymph nodes – as determined by BrdU incorporation – was increased 2.6- and 4.8-fold upon exposure to 10% and 25% (w/w) 1,2-dimethylimidazole, respectively. Since all SI’s were above 1.6, an EC1.6 could not be calculated by interpolation (in a BrdU assay, an EC1.6 is used as the threshold for sensitization, rather than the EC3 used upon 3H-thymidine incorporation). However, Ryan et al. (2007) describe that an EC3 can be calculated by log-linear extrapolation using the two lowest test concentrations, provided that the lowest SI value approaches the value of 3 and that a linear dose-response exists. In analogy, an EC1.6 of 6.6%(w/w) can be derived for 1,2-dimethylimidazole (EC1.6 = 2^{log2(c) + [log2(a) – log2(c)]*(1.6-d)/(b-d)} where a=25, b=4.8, c=10 and d=2.6).
1,2-dimethylimidazole was not mutagenic in the Ames test, in an in vitro HPRT test, and in an in vitro micronucleus test. Therefore, 1,2-dimethylimidazole is considered to be non-mutagenic.


Reference:


Ryan C.A., Chaney J.G., Gerberick G.F., Kern P.S., Dearman R.J., Kimber I., Basketter D. (2007). Extrapolating local lymph node assay EC3 values to estimate relatively sensitizing potency. Cutaneous and Ocular Toxicology, 26: 135-145.


 


DNEL derivation


For acute/short-term, systemic toxicity, no DNEL needs to be derived for all routes of exposure, because the long-term DNELs are considered to ensure sufficient protection to prevent peak exposure.


Long term, systemic DNEL – exposure via inhalation (workers)


Using a conservative approach, a worker DNEL (long-term inhalation exposure) is calculated. This worker long-term DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).


No repeated dose inhalation toxicity study with the substance is available. Therefore, it was necessary to obtain a long-term inhalation DNEL by route-to-route extrapolation.


Step 1: PoD: NOAEL = 100 mg/kg bw/day


Step 2: Modification of PoD:


Standard respiratory volume, human (sRVhuman) for 8 hours: 6.7 m3


Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m3/kg bw


Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m3


Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50%/100 % (default)


Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker


Corrected NOAEC (inhalation) for workers:


= 100 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4


= 123.42 mg/m3


Step 3: Overall AF= 25


Intraspecies AF (worker): 5


Interspecies AF, remaining differences: 2.5


Dose response relationship AF: 1


Exposure duration AF: 2 (subchronic to chonic)


Whole database AF: 1


The OECD TG 408 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.


In conclusion, long term systemic inhalation DNEL, workers = 4.94 mg/m3. 


Derivation from the NOAEL = 120 mg/kg bw/d of the pre-natal developmental toxicity study, results in a higher LT systemic inhalation DNEL = 5.9 mg/m3. Thus, this effect is covered by the DNEL derived from the oral RDT study. 
- corrected NOAEC (dev.tox) = 120 mg/kg bw/d *0.5 *1/0.38 m3/kg bw/d *(6.7 m3/10 m3) *7 d/5 d = 148.1 mg/m3
- DNEL (dev.tox) = 148.1 mg/m3 / (1 *1 *1 *2.5 *5 *2 *1) = 5.9 mg/m3 
  AF for dose response relationship = 1 (NOAEL, adverse effects in higher dose observed),
  AF for exposure duration = 1 (default for a developmental toxicity study),
  AF for interspecies difference = 1 (default after oral inhalation extrapolation),
  AF for other interspecies differences = 2.5 (default),
  AF for intraspecies differences = 5 (default),
  AF for quality of whole data base = 2 (maternal range finder for an OECD414 study),
  AF for remaining uncertainties = 1 (default)


 


Long term, systemic DNEL- exposure via dermal route (workers)


No repeated dose dermal toxicity study with the substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.


For the derivation of the dermal systemic DNEL long-term an absorption of 25% is assumed (50% of the oral absorption). The acute LD50 after intraperitoneal injection for mice is approximately 300 mg/kg bw. In the LLNA, mice were exposed up to a dose of 50 µl 25% (w/w) 1,2-dimethylimidazole on three consecutive days. Since the animals – which all survived – weighed about 20 g, this amount is equivalent to 509 mg/kg bw (calculation based on the assumption that the density of the 25% formulation is the same as that of the vehicle, namely 0.815; [50 µl x 0.815 mg/µl x 0.25]/0.020 kg bw= 509 mg/kg bw). The penetration through the skin is therefore maximally 100 * 300/ 509 = 59%, but probably lower since the dermal LD50 will be higher than 509 mg/kg bw. QSAR model DERMWIN (part of the model EPI suite) results in an estimated Kp of 0.00264 cm/h. According to the user manual of the Danish QSAR database (May 2005) this indicates low dermal absorption. The comparison of the effects after dermal absorption in the LLNA versus the acute LD50 after ip administration supports this assumption of a low dermal absorption. Therefore, in a Weight of Evidence approach, the dermal absorption is considered to be 50% of the oral absorption.


Step 1: PoD: NOAEL = 100 mg/kg bw/day


Step 2: Modification into a correct starting point:


Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 50%/25 % (default)


Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker


Corrected NOAEL (dermal) for workers:


= 100 mg/kg bw/day x 1.4 x 2


= 280 mg/kg bw/day


Step 3: Overall AF= 100


Interspecies AF, allometric scaling (rat to human): 4


Interspecies AF, remaining differences: 2.5


Intraspecies AF (worker): 5


Dose-response relationship AF: 1


Exposure duration AF: 2


In conclusion, long term systemic dermal DNEL, workers = 2.8 mg/kg bw/day. 


Derivation from the NOAEL = 120 mg/kg bw/d of the pre-natal developmental toxicity study, results in a higher LT systemic dermal DNEL = 3.4 mg/kg bw/d. Thus, this effect is covered by the DNEL derived from the oral RDT study. 
- corrected NOAEL (dev.tox) = 120 mg/kg bw/d *7 d/5 d *2 = 336 mg/kg bw/d
- DNEL (dev.tox) = 336 mg/kg bw/d / (1 *1 *4 *2.5 *5 *2 *1) = 3.4 mg/kg bw/d 
  AF for dose response relationship = 1 (NOAEL, adverse effects in higher dose observed),
  AF for exposure duration = 1 (default for a developmental toxicity study),
  AF for interspecies difference = 4 (default),
  AF for other interspecies differences = 2.5 (default),
  AF for intraspecies differences = 5 (default),
  AF for quality of whole data base = 2 (maternal range finder for an OECD414 study),
  AF for remaining uncertainties = 1 (default)


 


Long term, local DNEL- exposure via dermal route (workers)


Risk Assessment of Skin Sensitization: The BASF Position, 2009


Uncertainty factors with regard to exposure conditions
The ECHA guidance suggests using uncertainty factors that modify the endpoint according to matrix effects and the human exposure situation (ECHA guidance R.8, 2008). The aim is to take into consideration the actual use of the substance that could influence the potency with regard to skin sensitization. This view was potentially inspired by the risk assessment for fragrance ingredients (Api et al., 2006). This approach has assigned product categories (e.g. different deodorants, creams, make-up products etc.) for which the site of application of the product (e.g. face) and the matrix used (e.g. oil/water emulsion) are known. Each product category was assigned an uncertainty factor to extrapolate from the animal test to the actual human situation.
In the case of most chemicals, the influence of these effects is either unknown or the chemical is used in multiple applications that preclude the use of specific uncertainty factors for matrix effects and/or the exposure situation relative to the animal study. Therefore, the BASF position is to disregard these factors while deriving the DNEL whereas they are though to be included in the exposure estimation. This approach allows the setting of a general DNEL which is not linked to a specific application.


Interspecies
There are different views on the threshold derived from local lymph node data. Whereas the ECHA guidance considers it to be the LOAEL for induction (ECHA guidance R.8, 2008), a number of other organizations were able to empirically show that the EC3 closely correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use in the current case the EC1.6 estimated from the LLNA study, expressed as dose per skin area, as a surrogate for the human sensitization threshold without the modification by uncertainty factors.


Intraspecies
It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term ‘sensitive subpopulations’ refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). All of these effects make up the intraspecies factor and a factor of 10 is thought to adequately address the combined influence of these effects


Reference:
- Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).
- Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients.Reg Toxicol Pharmacol52: 3-23.
- ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.


 

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:
DNEL (Derived No Effect Level)
Value:
0.5 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):
200
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used (OECD TG study with 3 doses).
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
Default for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the "General population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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

Because there are no consumer uses for 1,2 -dimethylimidazole, CAS 1739 -84 -0, no consumer DNELs were derived; except for the oral systemic long-term DNEL, which is necessary for the ecotoxicological assessment man via environment.


 


Derivation from the NOAEL = 120 mg/kg bw/d of the pre-natal developmental toxicity study, results in a higher LT systemic oral DNEL = 0.6 mg/kg bw/d. Thus, this effect is covered by the DNEL of 0.5 mg/kg bw/d derived from the oral RDT study (see above). 
- NOAEL (dev.tox) = 120 mg/kg bw/d (no correction)
- DNEL (dev.tox) = 120 mg/kg bw/d / (1 *1 *4 *2.5 *10 *2 *1) = 0.6 mg/kg bw/d 
  AF for dose response relationship = 1 (NOAEL, adverse effects in higher dose observed),
  AF for exposure duration = 1 (default for a developmental toxicity study),
  AF for interspecies difference = 4 (default),
  AF for other interspecies differences = 2.5 (default),
  AF for intraspecies differences = 10 (default),
  AF for quality of whole data base = 2 (maternal range finder for an OECD414 study),
  AF for remaining uncertainties = 1 (default)