Registration Dossier

Administrative data

Description of key information

Acute Toxicity oral: Wistar rats m/f, oral: gavage, 2000 mg/kg bw (OECD 401, EU method B.1, GLP): LD50 > 2000 mg/kg, LD0 ≥ 2000 mg/kg, no animal died during study duration,no symptoms of poisoning were observed, no pathological findings

Acute Toxicity oral: oral: gavage, 1 or 2.5 g/kg bw to each 3 male rats:LD50 > 2500 mg/kg, LD0 ≥ 2500 mg/kg, no deaths noted, no symptoms of poisoning observed

Acute Toxicity inhalation: 1 cat, 1 rabbit, 1 guinea pig, 2 rats and 4 mice were exposed over 4h to the vaporated test item, mist, whole body,2.25 mg/L: LC0 ≥2.25 mg/L over 4h, no deaths, no animal regardless the species showed any signs of toxicity

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990-11-08 - 1991-02-08
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted under GLP according to EU method B.1 and OECD guideline 401 on the registered substance itself. The method is to be considered scientifically reasonable with negligible deficiencies in documentation.
Reference:
Composition 0
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
as set out in 84/449/EWG (1984-09-19)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted 1987-02-24
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
other: Wistar Bor: WISW (SPF Cpb)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Breeder Winkelmann, Borchen
- Age at study initiation: 8 weeks (males), 10 weeks (females)
- Weight at study initiation: average 185 g (males), 166 g (females), weight variation not exceeding ±20%
- Fasting period before study: yes, 16h prior to application
- Housing: In groups of five in Makrolon cages type III on low-dusting wood pellets
- Diet (e.g. ad libitum): "fixed-formula" standard diet Altromin® 1324 Pellets (Altromin GmbH und Co KG, Lage) ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 50 ± 10%
- Air changes (per hr): ca. 10/h
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg bw
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 / sex / dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: several times on application day, otherwise twice a day for clinical symptoms, weighing on day 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No animal died during study duration.
Key result
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No animal died during study duration.
Mortality:
No animal died during the 14-day observation period.
Clinical signs:
After single gavage of 2000 mg/kg bw no symptoms of poisoning were observed in males and females.
Body weight:
There were no effects on growth of males and females.
Gross pathology:
All animals killed after 14 days were without pathological findings.
Interpretation of results:
other: EU-GHS criteria not met
Conclusions:
The study was conducted under GLP according to EU method B.1 and OECD guideline 401 on the registered substance itself. The method is to be considered scientifically reasonable with negligible deficiencies in documentation. Hence, the results can be considered as sufficiently reliable to assess the acute oral toxicity in rats. The determined LD50 value is >2000 mg/kg bw, the LD0 ≥ 2000 mg/kg, as none of the animals died after gavage of 2000 mg/kg bw. The result is suitable to determine the classification of Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl). According to Regulation (EC) No. 1272/2008, the substance does not need to be classified as acute toxic cat. IV or higher.
Executive summary:

In an acute oral toxicity study under GLP according to EU method B.1 and OECD guideline 401, groups of fasted 8-10 weeks old Wistar Bor: WISW (SPF Cpb) rats (5/sex) were given a single oral dose of Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) in arachis oil at a limit dose 2000 mg/kg bw and observed for 14 days.

 

Oral LD50> 2000 mg/kg bw

Oral LD0≥ 2000 mg/kg bw

None of the animals died during the test or showed any signs of toxicity

 

Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) is of low toxicity based on the LD50 and does not need to be classified as acute toxic cat. IV or higher.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1959-03-16 - 1959-09-07
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Study conducted prior to GLP, no guideline followed as none was available in 1959, deficiencies in documentation. However, the available information allows the conclusion that the study was properly conducted with a scientifically acceptable method.
Reference:
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
The test item was applied orally by gavage at doses of 1 resp. 2.5 g/kg bw to each 3 male rats.
GLP compliance:
no
Remarks:
test conducted prior to GLP implementation
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
other: white
Sex:
male
Details on test animals and environmental conditions:
no data
Route of administration:
oral: gavage
Vehicle:
other: tragacanth
Details on oral exposure:
Test item was applied as aqueous tragacanth suspension.
Doses:
1 and 2.5 g/kg bw
No. of animals per sex per dose:
3 males per dose
Control animals:
no
Details on study design:
- Other examinations performed: clinical signs
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 500 mg/kg bw
Based on:
test mat.
Remarks on result:
other: highest dose tested, no symptoms of poisoning or deaths observed
Key result
Sex:
male
Dose descriptor:
LD0
Effect level:
>= 2 500 mg/kg bw
Based on:
test mat.
Remarks on result:
other: highest dose tested, no symptoms of poisoning or deaths observed
Mortality:
no deaths noted
Clinical signs:
no symptoms of poisoning observed
Interpretation of results:
other: EU-GHS criteria not met
Conclusions:
The study was conducted prior to GLP on the registered substance itself. The method is to be considered scientifically reasonable with some deficiencies in documentation. Hence, the results can be considered as sufficiently reliable to support the results revealed in the key study on the substance‘ acute oral toxicity in rats. The determined LD50 value is >2500 mg/kg bw, the LD0 ≥ 2500 mg/kg, as none of the animals died after gavage of 2500 mg/kg bw or showed signs of toxicity. The result is suitable to support the determination of the classification of 2,2'-Dioxy-3,3'-dicyclohexyl- 5-5'-dimethyl-diphenylmethan. According to Regulation (EC) No. 1272/2008, the substance does not need to be classified as acute toxic cat. IV or higher.
Executive summary:

In an acute oral toxicity study prior to GLP conducted with a scientifically reasonable method, groups of 3 white male rats were given a single oral dose of 2,2'-Dioxy-3,3'-dicyclohexyl- 5-5'-dimethyl-diphenylmethan in tragacanth at doses of 1000 and 2500 mg/kg bw.

 

Oral LD50> 2500 mg/kg bw

Oral LD0≥ 2500 mg/kg bw

None of the animals died during the test or showed any signs of toxicity.

 

2,2'-Dioxy-3,3'-dicyclohexyl- 5-5'-dimethyl-diphenylmethan is of low toxicity based on the LD50 and does not need to be classified as acute toxic cat. IV or higher.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
The study was conducted under GLP according to EU method B.1 and OECD guideline 401 on the registered substance itself. The method is to be considered scientifically reasonable with negligible deficiencies in documentation. Hence, the results can be considered as sufficiently reliable to assess the acute oral toxicity in rats. The determined LD50 value is >2000 mg/kg bw, the LD0 ≥ 2000 mg/kg, as none of the animals died after gavage of 2000 mg/kg bw. The result is suitable to determine the classification of Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl). This result is supported by another oral toxicity study consistently revealing no dead animal at a dose of 2500 mg/kg. Hence, the database is of high quality.

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to REACH Annex VIII column 2, 8.5.2. Testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.
The vapour pressure of the substance, extrapolated from experimental data is 9.48exp(-12) kPa at 20°C, 1.23exp(-9) kPa at 50°C, and 5.18exp(-9) kPa at 60°C (OECD 104). As it is a solid, no droplets of inhalable size will be formed, and due to the low vapour pressure no vapours need to be regarded. Although in reality not relevant due to appropriate safety precautions, direct dust exposure is excluded during handling, dust particles need to be regarded in theory: According to the particle size distribution, 0% of the particles belong to the respirable fraction (<4 µm), only 0.06% to the thoracic fraction (4-10 µm), and 40.11% of the particles are inhalable (10-100 µm).
The registrant concludes that testing is scientifically not necessary and would not reveal any additional information which cannot be derived from other available acute toxicity data, so that testing can be omitted due to animal welfare:
According to ECHA’s guidance, moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The determined LogPow is 6.3 at 23°C, lying clearly above that value and so hindering diffusion.
However, any lipophilic compound may be taken up by micellular solubilisation. This mechanism may be of particular importance for highly lipophilic compounds (Log Pow >4), particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed. This may be the case for 2,2´-Methylen-bis-(4-methyl-6-cyclohexylphenol). Based on the particle size distribution, only 40% of the orally applied dose would reach the body via inhalation, all other particles are too large to be bioavailable. Further, most of the particles are subject to nasal clearance, a minor portion to tracheobronchial clearance, and none of the particles are able to reach the alveoli. So, the availability of 40% of the applied dose as dust is considered a worst-case approach, and the design of a OECD 403 study (5 mg/l actual concentration of respirable substances) may overestimate the actual exposure.
Further, there are no signs of toxicity obvious via the oral or dermal route (LLNA). There is no study available fulfilling the criteria of an OECD 403 study (and required) for the acute inhalation toxicity of the test item; however, there is other information on acute toxicity available:

EU method B.1: LD50 > 2000 mg/kg, LD0 ≥ 2000 mg/kg, no animal died or showed symptoms of poisoning
No guideline, oral route: LD50, LD0 > 2500 mg/kg, none of the animals died or showed signs of toxicity

Due to the lack of relevant toxicity at the application of 2000 mg/kg bw of 2,2´-Methylen-bis-(4-methyl-6-cyclohexylphenol) via both the oral and dermal application route, and the fact that the LD50(oral) could only be determined as greater than 2000 mg/kg, the LD50(oral) > 2000 mg/kg bw will be further taken into account.
According to OECD guideline 403 (Acute inhalation toxicity), the concentration of respirable particles for limit testing is 5 mg/L over 4 h. Taking into account for rats a standard respiratory volume of 0.2 l/min and average body weight of 250 g (Guidance on information and requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012, ECHA, http://echa.europa.eu/web/guest/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment), a total respiratory volume of 48 litre over 4 h can be assumed. This would result in a total dose of 240 mg per rat, which is equivalent to 960 mg/kg bw.
Assuming in a worst-case scenario, although not relevant based on the phys.-chem. properties of the substance, that this total dose will be absorbed to 100%, and assuming furthermore that the orally applied amount is only absorbed to 50%, this dose would correspond to an oral dose of 1920 mg/kg bw. This is below the limit dose in oral and dermal tests and also below the actual LD50 via the oral application route, as only the limit dose of 2000 mg/kg was tested and led to no deaths or signs of toxicity in all dosed animals.
Hence, it can be reasonably assumed that an additional acute toxicity test via the inhalation route would reveal an LC50inhalation >5 mg/l.

So, in summary, it can be reasonably assumed that an additional testing for acute inhalation toxicity would not reveal any further relevant information and consequently, testing can be omitted due to animal welfare.
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
other information
Study period:
1959-03-16 - 1959-09-07
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Study conducted prior to GLP, no guideline followed as none was available in 1959, deficiencies in documentation, no analytical determination of the test concentration, mostly no standard species used.
Reference:
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
Animals were exposed over 4h to the vaporated test item
GLP compliance:
no
Remarks:
test conducted prior to GLP implementation
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
other: cat, rabbit, guinea pig, rat, mouse
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
1 cat, 1 rabbit, 1 guinea pig, 2 rats and 4 mice were exposed.
Route of administration:
inhalation: mist
Type of inhalation exposure:
whole body
Vehicle:
not specified
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure chamber volume: 400 L
- System of generating particulates/aerosols: heating of 20 g of the test item up to 150°C
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
4 h
Concentrations:
2.25 mg/L
No. of animals per sex per dose:
1 cat, 1 rabbit, 1 guinea pig, 2 rats and 4 mice
Control animals:
no
Details on study design:
- Other examinations performed: clinical signs
Sex:
not specified
Dose descriptor:
LC50
Effect level:
> 2.25 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: only dose tested, no animal regardless the species died during the study or showed signs of toxicity
Sex:
not specified
Dose descriptor:
LC0
Effect level:
>= 2.25 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: only dose tested, no animal regardless the species died during the study or showed signs of toxicity
Mortality:
none noted
Clinical signs:
no animal regardless the species showed any signs of toxicity
Interpretation of results:
relatively harmless
Remarks:
Criteria used for interpretation of results: expert judgment
Conclusions:
Based on the available data, no absolute classification of the test item is possible. However, it can be stated that it does not need to be classified as acute toxic by inhalation category 1.
Executive summary:

In an acute inhalation toxicity study, 1 cat, 1 rabbit, 1 guinea pig, 2 rats and 4 mice were exposed by inhalation route to 2,2'-Dioxy-3,3'-dicyclohexyl- 5-5'-dimethyl-diphenylmethan for 4 hours to whole body at a concentration of 2.25 mg/L.

 

LC50> 2.25 mg/L

LC0≥ 2.25 mg/L

No animal regardless the species died during the study or showed signs of toxicity.

 

2,2'-Dioxy-3,3'-dicyclohexyl- 5-5'-dimethyl-diphenylmethan is classified as being of low toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Two GLP guideline acute oral toxicity studies are available, clearly indicting in combination with at least Klimisch 2 phys.-chem. data, that the substance is highly unlike to pose a hazard via inhalation.
This conclusion is supported by the available information on inhalation toxicity. 1 cat, 1 rabbit, 1 guinea pig, 2 rats and 4 mice were exposed over 4h to the vaporated test item at a concentration of 2.25 mg/L. No animal died, no animal regardless the species showed any signs of toxicity, clearly indicating that the test item is consistently over different exposure routes rather harmless and not acutely toxic. Hence, the database is of high quality.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to the later amendment of REACH, i.e. Commission Regulation (EU) 2016/863 of 31 May 2016, testing by the dermal route does not need to be conducted if:
— the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and
— no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation) or, in the absence of an in vivo study by the oral route, no systemic effects after dermal exposure are predicted on the basis of non-testing approaches (e.g. read across, QSAR studies).
The oral LD50 in rats is >2000 mg/kg, no animal died at 2000 mg/kg, no symptoms of poisoning were observed in males and females. No clinical signs were noted at both skin irritation and sensitization testing. In the latter, no symptoms of local skin irritation at the ears of the animals and no signs of systemic toxicity were observed during the study period.
Further, due to the high LogPow = 6.3, absorption through the skin may be diminished, as outlined in the subchapter “Toxicokinetics”, and the possibly notable effects are in general considered to be of a lesser extent compared to the ones revealed in oral application testing. So any testing via the dermal route is not considered to provide additional, valuable information.
Hence, testing can be waived.
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Reason / purpose:
data waiving: supporting information
Related information:
Composition 1
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Two GLP guideline acute oral toxicity studies are available, clearly indicting in combination with at least Klimisch 2 phys.-chem. data, that the substance is highly unlike to pose a hazard via dermal application. Hence, the database is of high quality.

Additional information

In all available studies consistently no indication is given that the substance would need to be classified as acute toxic or poses any relevant risk for humans, as the animal model is considered sufficient to assess the inherent hazard of the substance via the oral route, and to draw conclusions in combination with phys.-chem. data on the inhalatory or dermal route. Testing for toxicity via inhalation or dermal application according to recent guidelines was considered not necessary as it would reveal no additional information and is also scientifically not relevant due to the intrinsic properties of the test item, e.g. low vapour pressure, or high lowPow. The tonnage-driven data requirements are hence fully met, no data gaps were identified, and the substance does not need to be classified as acute toxic.

Justification for classification or non-classification

All available studies via the oral revealed consistently LD50 and even LD0 (≥) values above 2000 mg/kg, which is the limit value for classification. Also, the given physico-chemical and toxicological data give no indication that testing for acute inhalation toxicity would result in LC50 values below 5 mg/L, the relative harmlessness is confirmed by other available inhalation data. Further, the given physico-chemical and toxicological data and so estimated toxikokinetics data indicate no need for classification via the dermal route as acutely toxic if a study was performed. Hence, classification criteria are not met and2,2'-Methylen-bis-(4-methyl-6-cyclohexylphenol)does not need to be classified as acute toxic according to Regulation 1272/2008.