Registration Dossier

Administrative data

Description of key information

Acute oral toxicity:
Three studies are available for acute toxicity (2 GLP-compliant studies) of members of the diphenylmethane category.
For SAS-40 the acute oral LD50 was estimated according to OECD guideline 401 to be 2531 mg/kg bw (GLP).
For 1,1-DPE the acute LD50 was estimated according to OECD guideline 401 to be > 8000 mg/kg (GLP).
For SAS-296 the acute oral LD50 was estimated in a non-GLP study similar to OECD 401.
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.
Acute dermal toxicity:
For SAS-40 the acute dermal LD50 was estimated in a GLP-compliant study according to OECD 402 ro be > 2000 mg/kg bw.
For SAS-305 the acute dermal LD50 was determined to be > 2000 mg/kg bw in a GLP-compliant study according to OECD guideline 402.
For 1,1-DPE a GLP-compliant study according to OECD 402 is available. The dermal LD50 was estimated to be > 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:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1990-03-01 - 1990-05-02
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
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
The animal room was maintained at a temperature of 19 - 28°C and relative humidity of 40 - 75%. On one occasion the temperature was above the upper limit specified in the protocol. This did not affect the purpose or integrity of the study. The rate of air exchange was approximately 15 changes per hour and the lighting was controlled by a time switch to give 12 hours light and 12 hours darkness.
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
All animals were dosed once only at the appropriate dose level by gavage using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to its fasted bodyweight at the time of dosing.
Doses:
Range-finding Study:
500, 1000, 3000, 5000 mg/kg

Main Study a:
5000 mg/kg

Main Study b:
Due to mortalities obtained, additional groups of ten animals, (five males and five females) were treated at logarithmically spaced dose levels as follows:
2324, 3000, 3873 mg/kg
No. of animals per sex per dose:
Range-Finding Study:
1 male and 1 female per dose

Main Study:
5 males and 5 females per dose
Control animals:
no
Details on study design:
Animals were observed 1 and 4 hours after dosing and subsequently once daily for 14 days. Deaths and evidence of overt toxicity were recorded at each observation.

Individual bodyweights were recorded on the day of treatment (day 0), days 7 and 14, or at death.

All animals were subjected to gross necropsy examination for any macroscopic abnormalities. No tissues were retained.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 531 mg/kg bw
Based on:
test mat.
95% CL:
1 927 - 3 324
Mortality:
Dose level: 2324 mg/kg: 3/10
3000 mg/kg: 7/10
3873 mg/kg: 9/10
5000 mg/kg: 9/10
Clinical signs:
Signs of toxicity noted in all dose groups were hunched posture and pilo-erection. Animals treated with 2324, 3873 or 5000 mg/kg also showed red/brown stains around the snout, red/brown stains around the mouth and/or ataxia. Incidents of pallor of the extremities, loss of righting reflex, decreased respiratory rate and lethargy were noted in animals treated with 3000 mg/kg or greater. Incidents of ptosis and increased salivation were also noted in one male treated with 3873 mg/kg and two females treated with 5000 mg/kg showed dehydration or diuresis. All males and one female treated with 2324 mg/kg appeared normal throughout the study. All other surviving animals appeared normal three or four days after dosing.
Body weight:
One female treated with 2324 mg/kg, one female treated with 3000 mg/kg and the surviving males treated with 3873 or 5000 mg/kg all showed a reduced bodyweight gain during the study.

All other animals showed expected gain in bodyweight during the study.
Gross pathology:
Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark or pale liver or patchy pallor of the liver, pale spleen, pale kidneys, haemorrhage of the glandular and non-glandular gastric epithelia and haemorrhage of the small and large intestines.

No abnormalities were noted at necropsy of animals killed at the end of the study except for pale livers noted in two females treated with 2324 mg/kg.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) and 95% confidence limits of the test material, NISSEKI-SAS-40, in the Sprague-Dawley strain rat were estimated to be:

All animals : 2531 (1927 - 3324) mg/kg bodyweight

Males only : 2726 (2379 - 3125) mg/kg bodyweight

Females only : 2180 (1009 - 4710) mg/kg bodyweight
Executive summary:

A study was performed to determine the acute oral median lethal dose (LD50) of the test material, administered undiluted, in the Sprague-Dawley strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals (1981) No. 401 "Acute Oral Toxicity" referenced as Method B1 in Annex V of EEC Commission Directive 84/449/EEC. Following a range-finding study, four groups, each of ten fasted animals (five males and five females), were given a single oral dose of undiluted test material at dose levels of 2324 to 5000 mg/kg bodyweight. Deaths were noted one to four days after dosing. Common signs of toxicity noted were hunched posture and pilo-erection. Additional or isolated incidents of toxicity noted were ataxia, lethargy, red/brown stains around the snout, red/brown stains around the mouth, pallor of the extremities, loss of righting reflex, decreased respiratory rate, ptosis, increased salivation, dehydration and diuresis. Surviving animals appeared normal throughout the study or three or four days after dosing. Incidents of reduced bodyweight gain were noted during the study. Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark or pale liver or patchy pallor of the liver, pale spleen, pale kidneys, haemorrhage of the glandular and non-glandular gastric epithelia and haemorrhage of the small and large intestines. No abnormalities were noted at necropsy of animals killed at the end of the study except for pale livers noted in two females treated with 2324 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 531 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
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Crl:WI(Han)
Sex:
male/female
Details on test animals or test system 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:
0.001 mg/m³
Quality of whole database:
The key study is GLP-compliant and has Klimisch score 2.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1990-03-29 - 1990-04-30
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
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
The animal room was maintained at a temperature of 20 - 24°C and relative humidity of 40 - 56%. The rate of air exchange was approximately 15 changes per hour and the lighting was controlled by a time switch to give 12 hours light and 12 hours darkness.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Approximately twenty-four hours prior to the commencement of the test the back and flanks of each animal were clipped free of hair using veterinary clippers to expose a skin area of approximately 5 cm x 4 cm.

The calculated volume of the undiluted test material, as received, was applied uniformly to an area of shorn skin approximating to 10% of the total body surface area using a graduated syringe. A piece of surgical gauze measuring 7 cm x 4 cm was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage (HYPERTIE). The bandage was further secured with a piece of BLENDERM wrapped around each end. The animals were housed individually during the exposure period.

Shortly after dosing the dressings were checked. After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material. The animals were then returned to group housing.
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 males and 5 females
Control animals:
not required
Details on study design:
All animals were observed for overt signs of toxicity and death 1 and 4 hours after dosing and subsequently at least once daily for fourteen days.

Individual bodyweights were recorded on the day of treatment (day 0) and on days seven and fourteen.

All animals were subjected to a gross necropsy examination for any macroscopic abnormalities. No tissues were retained.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
No evidence of systemic toxicity or skin irritation were noted during the study.
Body weight:
Individual bodyweights, together with weekly bodyweight gains, are given in Table 2.

All animals showed expected gain in bodyweight during the study period.
Gross pathology:
No abnormalities were noted at necropsy of animals killed at the end of the study.

For category rationale and justification see attached category documentation under section 13 "Assessment Reports".

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal median lethal dose (LD50) of the test material, NISSEKI - SAS -40, in the Sprague-Dawley strain rat was found to be greater than 2000 mg/kg bodyweight.
Executive summary:

A study was performed to assess the acute dermal toxicity of the test material in the Sprague-Dawley strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals (1981) No. 402 "Acute Dermal Toxicity" referenced as Method B3 in Annex V of EEC Commission Directive 84/449/EEC.

A group of ten animals (five males and five females), was given a single, 24-hour, semi-occluded dermal application of the test material to intact skin, at a dose level of 2000 mg/kg bodyweight.

There were no deaths. No evidence of systemic toxicity or skin irritation were noted during the study.

All animals showed expected gain in bodyweight during the study period.

No abnormalities were noted at necropsy of animals killed at the end of the study.

The acute dermal median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat was found to be greater than 2000 mg/kg body- weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The key study is GLP-compliant and has Klimisch score 2.

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 SAS-40 the acute oral LD50 was estimated according to OECD guideline 401 to be 2531 mg/kg bw (GLP).
For 1,1-DPE the acute LD50 was estimated according to OECD guideline 401 to be > 8000 mg/kg (GLP).
For SAS-296 the acute oral LD50 was estimated in a non-GLP study similar to OECD 401.
Overall, all measured acute oral toxicity data are very consistent. The study with the lowest LD50 and the highest quality is read across to Benzyltoluene and is taken for the risk assessment (SAS-40). No further testing is required. For detailed read across rationale and justification within the diphenylmethane category see section 13, Read across document.

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 Benzyltoluene.No further testing is required. For detailed read across rationale and justification within the diphenylmethane category see section 13, Read across document.

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 SAS-40 the acute dermal LD50 was estimated in a GLP-compliant study according to OECD 402 ro be > 2000 mg/kg bw.
For SAS-305 the acute dermal LD50 was determined to be > 2000 mg/kg bw in a GLP-compliant study according to OECD guideline 402.
For 1,1-DPE a GLP-compliant study according to OECD 402 is available. The dermal LD50 was estimated to be > 4 ml/kg.
The lowest LD50 is read across to Benzyltoluene. For detailed read across rationale and justification within the diphenylmethane category see section 13, Read across document.

Justification for classification or non-classification

Acute oral toxicity:

The respective criteria are not met.

The estimated LD50 of 2531 mg/kg bw. (read across from SAS-40) is well above the treshold for hazard category 4 (2000 mg/kg bw). Benzyltoluene 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 > 2000 mg/kg bw. (read across from SAS-40) is above the treshold for hazard category 4 (2000 mg/kg bw). Benzyltoluene is therefore not classified for acute dermal toxicity.

For detailed read across rationale and justification within the diphenylmethane category see section 13, Read across document.