Registration Dossier

Administrative data

Description of key information

Acute oral toxicity:
1,1-DPE was tested for acute oral toxicity according to OECD guideline 401 in groups of 3 male rats. Administration of up to 8.0 ml/kg orally resulted only in non-specific signs of treatment
The acute oral LD50 of 1,1-DPE was determined as > 8 ml/kg bw.
Acute toxicity via the inhalation route:
1,1-DPE was tested for acute toxicity via the inhalation route in a study similar to OECD guideline 403 for 1 hour.Two 1-hour exposures of 4 male rats/exposure to vapor of the test material generated at room temperature (calculated to contain 1.6 and 1.5 mg/l based on weight of samples before and after exposures) resulted in slight, transient eye irritation. At the end of the exposure period the rats were somewhat excitable. However, all rats appeared healthy and gained weight during the 2-week observation period. No lesions attributable to exposure to the test material were observed upon gross pathological examination 2 weeks after exposure.
Phenyl-tolyl-ethane was tested for acute toxicity via the inhalation route in a study according to OECD guideline 403 for 4 hours to two groups of five male and five female Wistar rats each group.The inhalatory LC50, 4h value of Phenyl-tolyl-ethane in Wistar rats was established to be within the range of 1 – 5 mg/L.
Acute dermal toxicity:
1,1-DPE was tested for acute dermal toxicity according to OECD guideline 402 in groups of 3 male rats. Administration of up to 4.0 ml/kg dermally resulted only in non-specific signs of treatment which were absent after 3 days. The acute dermal LD50 was established as > 4 ml/kg.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was conducted according to GLP and sufficient data is available for interpretation of results.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Not applicable
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Sprague Dawler CFY
Sex:
male
Details on test animals and environmental conditions:
Source: Interfauna (UK) Limited, Wyton, Huntingdon, Cambridgeshire

The animals were housed in groups of three in solid floor polypropylene cages furnished with softwood sawdust. The animal room temperature were maintained at 19 to 25°C with 40 to 70% relative humidity. Artifical lighting provided 12 hours light and 12 hours darkness. The animals were acclimatised for at least three days before treatment and individually identified by ear punching and cage card. With the exception of an overnight fast immediately before treatment the animals had free access to food (Rat and Mouse Expanded Diet No. 1, Special Diet Services Limited, Witham, Essex, UK). Water was provided at all times from glass water bottles.
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Five groups, each of three fasted male rats were treated with dose levels of 8.0, 4.0, 2.0, 1.0 or 0.5 ml/kg or g/kg. Liquid test materials were used
undiluted.
Doses:
0.5, 1.0, 2.0, 4.0 or 8.0 ml/kg
No. of animals per sex per dose:
3 male rats/dose
Control animals:
no
Details on study design:
Five groups, each of three fasted male rats were treated with dose levels of 8.0, 4.0, 2.0, 1.0 or 0.5 ml/kg or g/kg. Liquid test materials were used
undiluted. Animals were observed for overt systemic toxicityy and mortality one and four hours after dosing and then at least once daily for seven days. Individual bodyweights were recorded on the day of treatment. No necropsies were performed. Using the mortality data an estimate of the acute oral LD50 of the test material was made.
Statistics:
None
Preliminary study:
No data
Sex:
male
Dose descriptor:
LD50
Effect level:
> 8 mL/kg bw
Mortality:
No mortality
Clinical signs:
Animals at all dose levels showed hunched posture and pilo-erection on the day of dosing. Lethargy, decreased respiratory rate and ptosis were also noted in animals treated with 4.0 and 8.0 ml/kg.

Animals treated with 2.0 ml/kg and below recovered to appear normal on day one. Hunched posture and pilo-erection persisted on day one in the 4.0 ml/kg dose group and animals treated with 8.0 ml/kg showed hunched posture, lethargy, pilo-erection and decreased respiratory rate at this time. All animals appeared normal by day two and no further signs of toxicity were noted during the study period.
Body weight:
No data
Gross pathology:
No data
Other findings:
None

None

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU GHS
Conclusions:
The estimated acute oral LD50 in the male rat was greater than 8.0 ml/kg.
Executive summary:

Untreated DPE 75 (75% diphenyl ethane), a potential thermal oil, was provided for toxicity, testing by the Olefin Derivatives Department, DCE. It was tested for oral and dermal toxicity in groups of 3 male rats. Administration of up to 8.0 ml/kg orally resulted only in non-specific signs of treatment which were absent after 3 days.

Untreated DPE75 has very low toxicity by the oral route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
8 000 mg/kg bw
Quality of whole database:
The key study is GLP-compliant and of high quality (Klimisch 1).

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2011-11-18 - 2012-01-26
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The GLP study was conducted according to an internationally accepted guideline. All study parameters are given in detail. Nevertheless, according to the ECHA's practical guide 6: "How to report read-across and categories" the maximum for read-cross is 2.
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Crl:WI(Han)
Sex:
male/female
Details on test animals and environmental conditions:
Conditions
Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 ± 3.0°C (actual range: 19.6 - 21.9°C), a relative humidity of 40-70% (actual range: 40 - 56%) and 12 hours artificial fluorescent light and 12 hours darkness per day.

Accommodation
Before exposure
Group housing of five animals per sex per cage in labelled Makrolon cages (type IV; height 18 cm) containing sterilised sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.

After exposure
Group housing as described above, except that a paper sheet was introduced into the cage covering the bedding and cage enrichment to prevent suffocation in case of bad health condition. At the end of the Day of exposure the paper sheet was removed.

Diet
Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) except during exposure to the test substance.

Water
Free access to tap water except during exposure to the test substance.

Animal husbandry on the Day of exposure
The animals were moved to the inhalation area to in order to perform the exposure. During the exposure, there was no access to food and water. After exposure, the animals were returned their cages which were placed in a fume cupboard for a short time period to allow test substance remnants to evaporate. A sheet of filter paper was used to cover the bedding material to prevent suffocation in case of bad health condition and in order to recover and to aid the clinical observations. The sheet was removed and before the end of the exposure day, the animals were returned to the animal room.
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
The design of the exposure chamber is based on the flow past nose-only inhalation chamber (Am. Ind. Hyg Assoc. J. 44(12): 923-928, 1983). The chamber consisted of three animal sections with eight animal ports each. Each animal port had its own atmosphere inlet and exhaust outlet. The animals were placed in restraining tubes and connected to the animal ports. The number of animal sections and number of open inlets were adapted to the air flow in such a way that at each animal port the theoretical air flow was at least 1 L/min, which ensures an adequate oxygen supply to the animals. The main inlet of the test atmosphere was located at the top section and the main outlet was located at the bottom section. The direction of the flow of the test atmosphere guaranteed a freshly generated atmosphere for each individual animal.
All components of the exposure chamber in contact with the test material were made of stainless steel, glass, rubber or plastic. To avoid exposure of the personnel and contamination of the laboratory the exposure chamber was placed in a fume hood, which maintained at a slight negative pressure.
Fifteen minutes after the last animal was placed the generation of the test atmosphere was started. The exposure time was 4 hours.

Test atmosphere generation
The test substance was transferred to a nebulizer (LC SPRINT Baby rood, Pari, Starnberg, Germany) by means of a rotating pump (type VL500 digit, VERDER Lab Tec GmbH & Co. KG, Haan, Germany) and nebulized with pressurized air. The primary aerosol was diluted with humidified pressurized air and passed through the exposure chamber. The mean total airflow was 19 L/min for the 5 mg/L exposure group and 34 L/min for the 1 mg/L exposure group.
From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Target concentrations were based on the cut off concentration values specified in the UN and EC classification guidelines. Five animals of each sex were initially exposed in a limit test for 4 hours to a target concentration of the test substance of 5 mg/L. Based on the mortality observed, five animals of each sex were exposed to the next lower target concentration of 1 mg/L.
No. of animals per sex per dose:
5 male and 5 females per dose group.
Control animals:
no
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1 - < 5 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
At 5 mg/L, on the day following exposure (Day 2) three males and two females were found dead and the remaining animals were sacrificed for ethical reasons.
At 1 mg/L, one female was sacrificed for ethical reasons on Day 2. No further mortality occurred.
Clinical signs:
other: At 5 mg/L, the animals showed gasping and laboured respiration during exposure. After exposure, hunched posture, lethargy, flat posture, laboured respiration, piloerection, ptosis and/or moribund status were shown by the animals. At 1 mg/L, no clinical si
Body weight:
At 5 mg/L, body weights loss was noted in the animals found dead or sacrificed on Day 2. At 1 mg/L, overall body weight gain and body weight loss in males and females was within the range expected for rats of this strain and age used in this type of study.
Gross pathology:
At 5 mg/L, macroscopic post mortem examination of the animals that were found dead or sacrificed for ethical reasons during the study revealed abnormalities of the lungs (many dark red foci), stomach (black foci in the glandular mucosa), liver (pale discoloration) and mandibular lymph nodes (dark red discoloration). At 1 mg/L, no abnormalities were found at macroscopic post mortem examination of the animals.
Incidental findings included advanced autolysis which is not toxicologically relevant and pelvic dilation of the kidneys which is occasionally seen among rats of this age and strain and therefore considered not related to treatment.

The Mass Median Aerodynamic Diameter (MMAD) and geometric standard deviation (gsd) were determined twice. For the 5 mg/L exposure group, the MMAD was 2.9 μm (gsd 1.9) and 2.6 μm (gsd 2.1). For the 1 mg/L exposure group, the MMAD was 2.8 μm (gsd 2.1) and 2.9 μm (gsd 1.9).

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The inhalatory LC50, 4h value of Phenyl-tolyl-ethane in Wistar rats was established to be within the range of 1 – 5 mg/L.
Executive summary:

Phenyl-tolyl-ethane was administered as an aerosol by inhalation for 4 hours to two groups of five male and five female Wistar rats each group. Animals were subjected to daily observations and determination of body weights on Days 1, 2, 8 and 15. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).

At 5 mg/L, on the day following exposure (Day 2) three males and two females were found dead and the remaining animals were sacrificed for ethical reasons. At 1 mg/L, one female was sacrificed for ethical reasons on Day 2. No further mortality occurred. At 5 mg/L, the animals showed gasping and laboured respiration during exposure. After exposure, hunched posture, lethargy, flat posture, laboured respiration, piloerection, ptosis and/or moribund status were shown by the animals. At 1 mg/L, no clinical signs were noted during exposure. After exposure, the animals showed lethargy, hunched posture, piloerection and/or ptosis between Days 1 and 4. In addition, the female sacrificed on Day 2 showed uncoordinated movements, chromodacryorrhoea, hypothermia, shallow respiration and a lean appearance. At 5 mg/L, body weights loss was noted in the animals found dead or sacrificed on Day 2. At 1 mg/L, overall body weight gain and body weight loss in males and females was within the range expected for rats of this strain and age used in this type of study. At 5 mg/L, macroscopic post mortem examination of the animals that were found dead or sacrificed for ethical reasons during the study revealed abnormalities of the lungs (many dark red foci), stomach (black foci in the glandular mucosa), liver (pale discoloration) and mandibular lymph nodes (dark red discoloration). At 1 mg/L, no abnormalities were found at macroscopic post mortem examination of the animals. The inhalatory LC50, 4h value of Phenyl-tolyl-ethane in Wistar rats was established to be within the range of 1 – 5 mg/L.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
1 600 mg/m³
Quality of whole database:
The key study is GLP-compliant and has Klimisch score 1.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was conducted according to GLP and sufficient data is available for interpretation of results.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Sprague Dawley CFY
Sex:
male
Details on test animals and environmental conditions:
Sprague Dawley CFY rats obtained from Interfauna (UK) Limited, Wyton, Huntingdon, Cambridgeshire, were used.

The animals were housed in groups of three in solid floor polypropylene cages furnished with softwood sawdust. The animal room temperature was maintained at 19 to 25°C with 40 to 70% relative humidity. Artificaial lighting provided 12 hours light and 12 hours darkness. The animals were acclimatised for at least three days before treatment and individually identified by ear punching and cage card. The animals had free access to food (Rat and Mouse Expanded Diet No. 1, Special Diet Services Limited, Witham, Essex, UK). Water was provided at all times from glass water bottles.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Four groups, each of three male rats were given a single 24-hour, occluded dermal application to the shaved back at dose levels of 0.05, 1.0, 2.0 or 4.0 ml/kg or g/kg. Liquid testmaterial was used undiluted. The test site was covered with aluminium foil and secured by adhesive tape.
Duration of exposure:
24 hours
Doses:
0.05, 1.0, 2.0 or 4.0 ml/kg
No. of animals per sex per dose:
3 male rats/dose
Control animals:
no
Details on study design:
Four groups, each of three male rats were given a single 24-hour, occluded dermal application to the shaved back at dose levels of 0.05, 1.0, 2.0 or 4.0 ml/kg or g/kg. Liquid testmaterial was used undiluted. The test site was covered with aluminium foil and secured by adhesive tape.

Animals were observed for overt systemic toxicity and mortality one and four hours after dosing and then at least once daily for seven days. Individual bodyweights were recorded on the day of treatment. No necropsies were performed.

Using the mortality data an estimate of the acute dermal LD50 of the test material was made.
Statistics:
None
Preliminary study:
No data
Sex:
male
Dose descriptor:
LD50
Effect level:
> 4 mL/kg bw
Mortality:
No mortality
Clinical signs:
Animals treated with 4.0 ml/kg showed signs of toxicity on the day of dosing including lethargy, decreased respiratory rate, vocalisation, increased lacrimation and red/brown staining around the eyes and snout. All animals in the 2.0 m l /kg dose group showed lethargy and vocalisation at the one hour observation and vocalisation was also noted in one animal treated with 1.0 ml/kg one and four hours after treatment.

Hunched posture, pilo-erection and decreased respiratory rate persisted in the animals from the 4.0 ml/kg dose group on days one and two. Vocalisation was also apparent in one of these animals on day one. Animals in this group recovered to appear normal on day three and the affected animals from the other groups appeared normal four hours after treatment or on day one. No further signs of toxicity were noted during the study period. There was no evidence of systemic toxicity in animals treated with 0.5 ml/kg.


Body weight:
No data
Gross pathology:
No data
Other findings:
None

None

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU GHS
Conclusions:
The estimated acute dermal LD50 in the male rat following a single, 24 hour, occluded application to intact skin was greater than 4.0 ml/kg.
Executive summary:

Untreated DPE 75 (75% diphenyl ethane), a potential thermal oil, was provided for toxicity, testing by the Olefin Derivatives Department, DCE. It was tested for oral and dermal toxicity in groups of 3 male rats. Administration of up to 4.0 ml/kg dermally resulted only in non-specific signs of treatment which were absent after 3 days.

Skin irritation studies were performed with 3 New Zealand White rabbits in each case. A 4 hour dermal application of 0.5 ml/kg resulted in erythema and oedema in all rabbits which lasted for more than 3 days but had recovered by 7 days.

Untreated DPE75 has very low toxicity by dermal routes.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 000 mg/kg bw

Additional information

No data gaps were identified. The available data are adequate for risk assessment and classification and labelling purposes.


Justification for selection of acute toxicity – oral endpoint
Three studies are available for acute toxicity (2 GLP-compliant studies) of members of the diphenylmethane category.
For 1,1-DPE the acute LD50 was estimated according to OECD guideline 401. The determined LD50 of > 8000 mg/kg is used for the risk assessment of 1,1-DPE.
Overall, all measured acute oral toxicity data are very consistent. No further testing is required. For detailed category rationale and justification see section 13, category justification.

Justification for selection of acute toxicity – inhalation endpoint
Two studies are available for members of the diphenylmethane category for acute toxicity via the inhalation route.
For Phenyl-tolyl-ethane the LC50 was estimated in a GLP-compliant study according to OECD 403. A LC50 of 1-5 mg/l was determined.
The acute toxicity of 1,1-DPE was assessed in a non GLP-compliant study according to OECD guideline 403. The determined LC50 was >1.6 mg/l.
Since the study results are in the same order of magnitude the study with Phenyl-tolyl-ethane (highest quality) is used for the risk assessment of 1,1-DPE.No further testing is required. For detailed category rationale and justification see section 13, category justification.

Justification for selection of acute toxicity – dermal endpoint
Three studies are available for members of the diphenylmethane category for acute dermal toxicity. All measured acute dermal toxicity data are very consistent (LD50 > 2000 mg/kg bw.).
For 1,1-DPE a GLP-compliant study according to OECD 402 is available. The dermal LD50 was estimated to be > 4 ml/kg.

Justification for classification or non-classification

Acute oral toxicity:

The respective criteria are not met.

The estimated LD50 of > 8000 mg/kg bw. is well above the treshold for hazard category 4 (2000 mg/kg bw). 1,1 -DPE is therefore not classified for acute oral toxicity.

Acute toxicity via the the inhalation route:

The respective criteria are met. The estimated LC50 of 1 - 5 mg/l (read across from PTE) justifies the classification as acute toxic via the inhalation route, category 4.

Acute dermal toxicity:

The respective criteria are not met.

The estimated LD50 of > 4000 mg/kg bw. is well above the treshold for hazard category 4 (2000 mg/kg bw). 1,1 -DPE is therefore not classified for acute dermal toxicity.