Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.4 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):
30
Explanation for the modification of the dose descriptor starting point:

Dose descriptor starting point: NOAEL (OECD422, rat, gavage) = 150 mg/kg bw/d

Modification:

- Ratio of inhalation to oral absoption: 2

- standard respiratory volume, rat, corrected for 8 h exposure: 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

Modified dose descriptor: NOAEC = 150 mg/kg bw/d /2 /0.38 m3/kg bw *(6 .7/10) = 132.2 mg/m3

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:
2.5 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):
120
Explanation for the modification of the dose descriptor starting point:

Relevant dose-descriptor: NOAEL (OECD422, rat, gavage) = 150 mg/kg bw/d

Modification:

- dermal to oral absorption: 50 % (see discussion)

Modified dose-descriptor: NOAEL = 150 mg/kg bw/d / 0.5 = 300 mg/kg bw/d

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

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. 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 combined 28-days repeated dose toxicity study with reproduction/developmental toxicity screening test, 1,2-dimethylimidazole was given to rats by oral gavage at dose levels of 15, 50, or 150 mg/kg/day. No treatment-related changes were observed up to the highest dose tested. Based on these results, a parental, reproduction and developmental NOAEL of at least 150 mg/kg bw/day was derived. In the preceding 14-day range finding study in which rats were exposed to 300 mg/kg bw/day 1,2‑dimethylimidazole by gavage, body weight loss was observed in both sexes and clinical abnormalities (lethargy, hunched posture and/or piloerection) were seen during the last 3-4 days of treatment.

 

Irritation / Sensitisation / Mutagenicity

1,2-dimethylimidazole is considered to be irritating to the skin and causes serious damage to the eyes. 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. 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)1 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.

 

1Ryan 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 short-term 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. Since there are no consumer uses for 1,2-dimethylimidazole, DNELs are derived only for workers.

- Oral: For long-term toxicity, regarding systemic effects, a NOAEL of 150 mg/kg bw/day was observed in a combined 28-day repeated dose toxicity study with reproduction/developmental toxicity screening test. This NOAEL is used in the derivation of the DNELs. An absorption of 50% is assumed for the oral route.

- Inhalation: In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 2 for oral-to-inhalation extrapolation was used as proposed inChapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from thecombined 28-day repeated dose toxicity study with reproduction/developmental toxicity screening testwas used for derivation of the systemic DNELlong-termfor the inhalation route.An absorption of 100% is assumed for the inhalation route.

- Dermal: Long-term dermal toxicity data are not available and therefore route-to-route extrapolation is performed.

For the derivation of the dermal systemic DNELlong-terman 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.

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:
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

Because there are no consumer uses for 1,2 -dimethylimidazole, CAS 1739 -84 -0, no consumer DNELs were derived.