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Administrative data

Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not 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
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 4.3×10^-7 hPa at 20 °C, 6.2×10^-7 hPa at 25 °C and 3.5× 10^-6 hPa at 50 °C. As it is a solid, no droplets of inhalable size will be formed. There are no particles of inhalable size formed because the substance is manufactured and used in a non solid/granular form (pastilles). So, direct dust exposure is excluded during handling, hence not fulfilling the above-mentioned criteria for the necessity of testing.
Furthermore, 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 7.1 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 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin, however, as no inhalable forms / particles are formed, micellular solubilisation may be disregarded.
Last but not least, there are no signs of toxicity obvious via the oral or dermal route. There is no study available (and required) for the acute inhalation toxicity of the test item; however, there are LD50 values via other application routes available:

EU method B.1, limit test: The determined oral LD50 value is >2000 mg/kg bw, the LD0 ≥ 2000 mg/kg in male rats, as only one female died after gavage of 2000 mg/kg bw.
No guideline, oral route: LD50, LD0 > 1000 mg/kg
OECD 402, limit test, semi-occlusive: LD0(dermal) ≥ 2000 mg/kg bw, LD50(dermal) > 2000 mg/kg bw, the animals did not show any general clinical signs. No pathological changes on the treated skin of males and females were found. All animals survived the experiment. No pathological changes on the treated skin or other signs of irritation were noted.

Due to the lack of relevant toxicity at the application of 2000 mg/kg bw of 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl-12H-dibenzo[d,g][1,3,2]dioxaphosphocin 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 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 those application routes, as only the limit dose of 2000 mg/kg was tested and led to the death of only one female 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.
Furthermore, during the investigation of the acute dermal toxicity, no alterations of the skin were detected, and the test item is neither a skin nor eye irritant. So it can be additionally concluded, that no local effects during inhalation toxicity testing are likely to occur and need to be regarded.

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.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988-04-26 - 1988-05-10
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study conducted under GLP according to EU method B.1 on the registered substance itself. The method is to be considered scientifically reasonable with negligible deficiencies and methodological variations due to the intrinsic properties of the test item, which are foreseen in the guideline.
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
as published in 84/449/EWG
Deviations:
yes
Remarks:
limit dose only 2000 mg/kg
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: strain Bor: WISW (Spf Cpb) from Breeder Winkelmann, Borchen, Germany
- Age at study initiation: 9 weeks (males), 14 weeks (females)
- Weight at study initiation (average): 172g (males), 173g (females), weight variation < ±20% of mean value
- Fasting period before study: 16h
- Housing: in groups of five in Makrolon cages Type III on dust-free wood pellets (Ssniff, Soest/Westfalen)
- Diet (e.g. ad libitum): fixed-formula standard diet Altromin 1324 Pellets (Altromin GmbH, Lage, Germany) ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: min. 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2°C
- Humidity (%): ca. 50±10%
- Air changes (per hr): ca. 10
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
400
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 20 ml/kg bw

MAXIMUM DOSE VOLUME APPLIED: 2 x 20 ml/kg bw

DOSAGE PREPARATION (if unusual): suspension
Doses:
2000 mg/kg, applied as 2 x 1000 mg/kg with a 6h interval
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: inspections twice daily (once on weekends and bank holidays), weighing prior application, after 1 week and at the end of the study
- 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.
Sex:
male
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
On the second day after treatment one female died.
Clinical signs:
other: Beginning ca. 1h after the first application of 1000 mg/kg a slightly ruffled fur was observed on all animals. This effect was rather slight and persisted until day 5 after application. One female was on the day after application in a poor general conditi
Gross pathology:
A pathological/anatomical examination of the dead female was not possible due to cannibalism.
All sacrificed animals at the end of the study were without pathological/anatomical findings.
Interpretation of results:
other: EU-GHS criteria not met
Conclusions:
The study was conducted under GLP according to EU method B.1 on the registered substance itself. The method is to be considered scientifically reasonable with negligible deficiencies and methodological variations due to the intrinsic properties of the test item, which are foreseen in the guideline. 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 in male rats, as only one female died after gavage of 2000 mg/kg bw. The result is suitable to determine the classification of 12H-Dibenzo(d,g)(1,3,2)dioxaphosphocin, 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl. According to Directive 79/831/EWG, no classification is required. 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, groups of fasted 9-14 weeks old Wistar Bor: WISW (SPF Cpb) rats (5/sex) were given a single oral dose of 12H-Dibenzo(d,g)(1,3,2)dioxaphosphocin, 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl (2 x 1000 mg/kg bw with 6h interval) in polyethylenglycol 400 at a limit dose of 2000 mg/kg bw and observed for 14 days.

 

Oral LD50> 2000 mg/kg bw

Oral LD0≥ 2000 mg/kg bw (males)

One female died during the test after 2 days. One hour after application, ruffled fur was observed in all animals and lasted until day 6. At the end of the test, all animals were without pathological/anatomical findings.

 

12H-Dibenzo(d,g)(1,3,2)dioxaphosphocin, 4,8-dicyclohexyl-6-hydroxy-2,10-dimethyl is of low Toxicity based on the LD50 and does not need to be classified as acute toxic cat. IV or higher.

Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015-06-17 - 2015-07-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP OECD 402 guideline study without deviations on the registered substance itself.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
OECD Guideline for the Testing of Chemicals No. 402 “Acute Dermal Toxicity” (adopted 24 February 1987)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
Method B3 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Department of Health of the Government of the United Kingdom
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Five male and five female Wistar (RccHan:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK.
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: At least 200 g, the weight variation did not exceed ±20% of the mean weight for each sex.
- Fasting period before study: no
- Housing: The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24 Hour exposure period and in groups of five, by sex, for the remainder of the study.
- Diet (e.g. ad libitum): 2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours continuous light (06:00 to 18:00) and 12 hours darkness
Type of coverage:
semiocclusive
Vehicle:
arachis oil
Remarks:
arachis oil BP
Details on dermal exposure:
TEST SITE
- Area of exposure: back and flanks
- % coverage: approx. 10% of the total body surface area
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- For solids, paste formed: yes, the test item was ground to a fine powder using a mortar and pestle, then weighed out according to each animal’s individual body weight and moistened with arachis oil BP prior to application
Duration of exposure:
24h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5/sex/dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 30 minutes, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days. Individual body weights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, other: evidence of primary irritation
Statistics:
An estimate of the acute dermal median lethal dose (LD50) of the test item was made.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: There were no deaths.
Key result
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: There were no deaths.
Mortality:
There were no deaths.
Clinical signs:
other: No signs of systemic toxicity were noted during the observation period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
- Other observations: Dermal Reactions: There were no signs of dermal irritation.

Tables for individual findings are attached.

Interpretation of results:
GHS criteria not met
Remarks:
EU implementation
Conclusions:
The study was conducted under GLP according to OECD guideline 402 on the registered substance itself. The method is to be considered scientifically reasonable with no deficiencies in documentation. Hence, the results can be considered as reliable to assess the acute oral toxicity in rats.
Following single application of CAS 73912-21-7 at a dose of 2000 mg/kg bw, the animals did not show any general clinical signs. No pathological changes on the treated skin of males and females were found. All animals survived the experiment. During the 14-day experiment, body weight gain was found in all animals. Gross examination did not reveal any pathological changes in the examined animals. So it may be stated that the median lethal dose (LD50) of CAS 73912-21-7 is greater than 2000 mg/kg b.w. Since no animal showed at no observation time any pathological changes on the treated skin or other signs of irritation, it may be concluded that, under the conditions of this test, CAS 73912-21-7, does not need to be considered as irritating to rat skin.
According to the Regulation (EC) No. 1272/2008, it may be concluded that CAS 73912-21-7 is beyond categorization.
Executive summary:

In an acute dermal toxicity study (OECD 402), groups of 8-12 weeks old Wistar (RccHan:WIST) rats (5/sex) were dermally exposed to CAS 73912-21-7 in Arachis oil BP for 24 hours on 10% of body surface area at a dose of 2000 mg/kg bw under semi-occlusive coverage. Animals then were observed for 14 days.

 

Following single application of the test item, the animals did not show any general clinical signs. No pathological changes on the treated skin of males and females were found. All animals survived the experiment. During the 14-day experiment, body weight gain was found in all animals. Gross examination did not reveal any pathological changes in the examined animals. Hence, the following results could be gained:

 

LD0(dermal) ≥ 2000 mg/kg bw

LD50(dermal) > 2000 mg/kg bw

 

CAS 73912-21-7 is of low Toxicity based on the LD50 determined. Since no animal showed at no observation time any pathological changes on the treated skin or other signs of irritation, it may be concluded that, under the conditions of this test, CAS 73912-21-7 should not be considered as irritating to rat skin.

According to Regulation (EC) No. 1272/2008, it may be concluded that CAS 73912-21-7 is beyond categorization.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion