Registration Dossier

Administrative data

Description of key information

Acute oral toxicity:

In absence of data on Tar acids, Xylenol fraction (CAS 84989-06-0) an analogue read-across approach was conducted:

WoE - mixed ethylphenols (RL1; according to OECD 425 and GLP; rat): LD50 980.62 mg/kg bw; NOEL 175 mg/kg bw;

WoE - mixed xylenols (RL1; according to OECD 425 and GLP; rat): LD50 980.62 mg/kg bw; NOEL 175mg/kg;

WoE - m-cresol (RL2; similar to OECD 401, no GLP; rat): LD50 242 mg/kg bw;

WoE - o-cresol (RL2; similar to OECD 401, no GLP; rat): LD50 121 mg/kg bw;

WoE - p-cresol (RL2; similar to OECD 401, no GLP; rat): LD50 207 mg/kg bw;

Acute inhalation toxicity:

Data base regarding acute inhalation toxicity is very limited and does not allow a final conclusion. Further testing is, however, not required, because Tar acids, Xylenol fraction (CAS 84989-06-0) is evaluated as corrosive, classified for acute dermal toxicity (Acute Tox. 3, H311) and is a crystalline solid. Therefore, no further testing is warranted according to REACH Regulation (EC) No 1907/2006, Annex VIII, Column 2.

Acute dermal toxicity:

In absence of data on Tar acids, Xylenol fraction (CAS 84989-06-0) an analogue read-across approach was conducted:

WoE - 3,5-xylenol (RL2; similar to OECD 402, no GLP; rat): LD50 > 2400 mg/kg bw;

WoE - m-cresol (RL2; no guideline study, no GLP; rabbit): LD50 2050 mg/kg bw;

WoE - o-cresol (RL2; no guideline study, no GLP; rabbit): LD50 1380 mg/kg bw;

WoE - p-cresol (RL2; no guideline study, no GLP; rabbit): LD50 301 mg/kg bw;

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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
no information on strain used, no information on statistical evaluation given
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
single application by gavage, 5 rats/dose group, 4 doses, undiluted liquid, time of recovery: up to 14 days, observations for signs of toxicity, necropsy at the end of the observation time
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
no data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
no further data
Doses:
147, 215, 316, 464 mg/kg bw
No. of animals per sex per dose:
5 male rats/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: daily; weighing at the beginning and at the end
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross autopsy of survivors and decedents
Statistics:
yes, method not described
Preliminary study:
no data
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 242 mg/kg bw
Based on:
test mat.
95% CL:
>= 190 - <= 308
Mortality:
see section"remarks on results including tables and figures"
Clinical signs:
onset: 0-4 hours: hypoactivity, tremor, convulsions, salivation, prostration, death (see section"remarks on results including tables and figures")
Body weight:
174 - 186 g initial body weight; terminal body weight ca. 224 g
Gross pathology:
survivors: no significant findings
decedents: inflammation of the gastrointesinal tract, hyperemia of lungs, liver, kidneys
see section"remarks on results including tables and figures"
Other findings:
no further data

Dosage

mg/kg bw

Onset of sympt

0-4hrs

Mortality

Mortality

cumulative

0-4hrs

day3

day6

day7

147

S

 

 

 

 

0/5

215

S

 

1/5

 

1/5

2/5

316

S

3/5

 

1/5

 

4/5

464

S

4/5

1/5

 

 

5/5

S = signs of intoxication: hypoactivity, tremors, convulsions, salivation, prostration

survivors: recovery within observation time, gross necropsy: no significant findings
decedents, gross necropsy: inflammation of the gastrointestinal tract, hyperemia of lungs, liver and kidneys

Interpretation of results:
other: CLP/EU GHS Category 3 (H301) according to Regulation (EC) No 1272/2008
Conclusions:
CLP: Acute tox 3, H 301
Executive summary:

Single oral application of undiluted testsubstance by gavage to 5 rats/dose group and an observation time up to 14 days resulted in an LD50 value of 242 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: individual animal data not given
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
5 male rats/dose, observed for symptoms and mortality up to 10 - 14 days, afterwards gross autopsy
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
no further data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
no further data
Doses:
68, 100, 147, 215 mg/kg bw
No. of animals per sex per dose:
5 male rats/dose
Control animals:
no
Details on study design:
no further details
Statistics:
yes, but method not mentioned
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
121 mg/kg bw
Based on:
test mat.
Mortality:
68 mg/kg bw: no deaths but signs of intoxication; recovery within 2 days
100 mg/kg bw: mortality: 2/5; survivors recovered within 4 days
147 mg/kg bw: mortality: 3/5; surviors recovered within 6 days
215 mg/kg bw: mortality: 5/5
Clinical signs:
All animals showed signs of intoxication including hypoactivity, tremor, convulsions, salivation, dyspnea, prostration within 4 hours post dosing
Body weight:
rat dosed 68 mg/kg bw: initial body weight: 195 g // terminal body weight: 219 g; no further terminal body weights given
Gross pathology:
At autopsy, survivors showed no significant findings, decedents showed hemorrhage of gastrointestinal tract, hyperemia of liver, kidneys and lungs
Other findings:
no further data
Interpretation of results:
other: CLP/EU GHS Category 3 (H301) according to Regulation (EC) No 1272/2008
Conclusions:
CLP: Acute tox 3, H 301
Executive summary:

To determine LD50-value 5 male rats/dose received single oral doses of 68, 100, 147, 215 mg/kg bw by gavage and were observed for symptoms and mortality for up to 10 - 14 days. Suvivors and decedents were examined afterwards by gross autopsy. LD50 was determined 121 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No information about strain used, GLP
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
5 rats/dose group, observed for symptoms for up to 14 d, afterwards gross autopsy
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
no further data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
no flurther data
Doses:
100, 147, 215, 316 mg/kg bw
No. of animals per sex per dose:
5 male rats/dose
Control animals:
no
Details on study design:
no further details
Statistics:
yes, but method not mentioned
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
207 mg/kg bw
Based on:
test mat.
95% CL:
>= 172 - <= 250
Mortality:
mortality occurred within 4 hours post dosing
100 mg/kg bw: 0/5; 147 mg/kg bw: 0/5; 215 mg/kg bw: 3/5; 316 mg/kg bw: 5/5
Clinical signs:
onset in all animals within the first 4 hours post dosing: hypoactivity, tremors, lacrimation, dyspnea, hemorrhagic rhinitis, convulsions, prostration, recovery occurred in all survivors
Body weight:
initial mean body weight ranged between 187 - 220 g, terminal mean body of the survivor-groups: 227 - 229 g (no further data)
Gross pathology:
Necropsy of the rats that died revealed gastrointestinal inflammation and haemorrhage and hyperaemia of the lungs, liver and kidney.  
Survivors showed only gastrointestinal tract inflammation.
Other findings:
no further data
Interpretation of results:
other: CLP/EU GHS Category 3 (H301) according to Regulation (EC) No 1272/2008
Conclusions:
CLP: Acute tox 3, H 301
Executive summary:

Following single oral doses to rats the LD50 was determined 207 mg/kg bw. The observed signs of intoxication included hypoactivity, tremors, lacrimation, dyspnea, hemorrhagic rhinitis, convulsions and prostration.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
15 March 2004 to 11 April 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
yes
Remarks:
see Principle of method if other than guideline
Principles of method if other than guideline:
Deviations:
The dosage, postdosage and scheduled sacrifice periods were each extended for an additional 3 days. 30 rats were received at the testing facility rather than the 20 rats stated in the protocol. Rat 5389 in the 550 mg/kg bw dosage group was given 3 h and 4 h observations at 4 h 39 mins and 4 h 46 mins, respectively. These deviations are not considered to adversely affect the study integrity.
GLP compliance:
yes
Remarks:
Quality assurance statement only.
Test type:
up-and-down procedure
Limit test:
no
Species:
rat
Strain:
other: Crl:CD(SD)IGS BR VAF/Plus
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, Michigan, USA
- Age at study initiation: 63 days (at arrival)
- Weight at study initiation: 197 - 223 g (the day after arrival)
- Fasting period before study: Fasted on the night before the dosage administration, with feed returned to the animals following the 4 h clinical observation.
- Housing: Individually housed in stainless-steel wire-bottomed cages.
- Diet (e.g. ad libitum): Certified Rodent Diet #5002 (PMI Nutrition International, Inc., St. Louis, Missouri, USA).
- Water (e.g. ad libitum): Local water, passed through a reverse osmosis membrane, available ad libitum, via individual water bottles. Chlorine was added to the processed water as a bacteriostat.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 64 - 79°F (18 - 26°C)
- Humidity (%): 30 - 70%
- Air changes (per hr): Positive airflow, minimum of 10 changes per hour of HEPA filtered air.
- Photoperiod (hrs dark / hrs light): 12 h dark / 12 h light

IN-LIFE DATES: From: 15 March 2004 To: 11 April 2004
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 35 mg/mL vehicle, 110 mg/mL vehicle and 350 mg/mL vehicle
- Amount of vehicle (if gavage): 5 mL/kg
- Justification for choice of vehicle: Not stated, guideline vehicle substance.
- Lot/batch no. (if required): 062K0006
- Purity: Not stated
Doses:
175, 550 and 1750 mg/kg bw
No. of animals per sex per dose:
All females, 1 rat for 175 mg/kg bw, 4 rats for 550 mg/kg bw, 4 rats for 1750 mg/kg bw.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Pre-dose, at least once in the 30 mins after dosage, approx. hourly intervals for the first 4 h and then daily thereafter for observations. Body weights were recorded weekly during acclimation, daily during the dosing and observation period and at sacrifice.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, feed consumption
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
980.62 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Calculated from log10 values.
Sex:
female
Dose descriptor:
other: NOEL
Effect level:
ca. 175 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Adverse clinical signs at 550 mg/kg bw
Mortality:
3 rats died in the 1750 mg/kg bw dose group from treatment related effects.
Clinical signs:
Clinical observations which were determined to be dose related included: lacrimation, excess salivation and urine stained fur in both the 550 and 1750 mg/kg bw dose groups. Decreased motor activity, twitches, prostrate, ptosis, limited use of hindlimbs, lost proprioceptive positioning, no use of both hind and forelimbs, ataxia, lost righting reflex, tachypnea, impaired righting reflex and scant faeces were observed in the 1750 mg/kg bw dose group.
Body weight:
Body weight changes were reduced in the 550 and 1750 mg/kg bw dose groups compared to the rat in the 175 mg/kg bw dose group. However, all surviving rats gained weight after dose administration.
Gross pathology:
Necropsy confirmed the clinical observations. No gross lesions were found.
Other findings:
Feed consumption values, both absolute (g/day) and relative (g/kg bw/day) showed a dose dependent reduction in the day after dosing in the 550 and 1750 mg/kg bw dose groups. This trend continued until day 5 post dosing, after which the values remaind comparative to the 175 mg/kg bw dosed animal.

Three rats in the 1750 mg/kg bw dose group were found dead during the study. Eight of the nine test animals showed dose related effects. There were no deaths in the 175 and 550 mg/kg bw dose groups. Clinical observations which were determined to be dose related included: lacrimation, excess salivation and urine stained fur in both the 550 and 1750 mg/kg bw dose groups. Decreased motor activity, twitches, prostrate, ptosis, limited use of hindlimbs, lost proprioceptive positioning, no use of both hind and forelimbs, ataxia, lost righting reflex, tachypnea, impaired righting reflex and scant faeces were observed in the 1750 mg/kg bw dose group. Necropsy confirmed the clinical observations. No gross lesions were found.

Body weight changes were reduced in the 550 and 1750 mg/kg bw dose groups compared to the rat in the 175 mg/kg bw dose group. However, all surviving rats gained weight after dose administration. Feed consumption values, both absolute (g/day) and relative (g/kg/day) showed a dose dependent reduction in the day after dosing in the 550 and 1750 mg/kg bw dose groups. This trend continued until day 5 post dosing, after which the values remaind comparative to the 175 mg/kg bw dosed animal.

Table 1: Mortality results of the up and down procedure with ethyl phenols

Step

Dose (mg/kg bw)

Response

Include

Log10 dose

1

175

O

No

-

2

550

O

Yes

2.740

3

1750

X

Yes

3.243

4

550

O

Yes

2.740

5

1750

X

Yes

3.243

6

550

O

Yes

2.740

7

1750

X

Yes

3.243

8

550

O

No

-

9

1750

O

No

-

Total

17.949

O = alive, X = dead
Sum of log10 doses/# of eligible rats: 17.949/6 = 2.9915, antilog of 2.9915 = 980.62 mg/kg bw = LD50

Table 2: Summary of observations of adverse effects during study

Observation

175 mg/kg bw

550 mg/kg bw

1750 mg/kg bw

Death

0

0

3

Lacrimation

0/0

1/1

4/4

Decreased motor activity

0/0

0/0

4/4

Twitches

0/0

0/0

3/3

Prostrate

0/0

0/0

3/3

Excess salivation

0/0

1/1

2/2

Ptosis

0/0

0/0

2/2

Limited use of hindlimbs

0/0

0/0

2/2

Lost proprioceptive positioning

0/0

0/0

2/2

No use of both hind and forelimbs

0/0

0/0

2/2

Ataxia

0/0

0/0

2/2

Lost righting reflex

0/0

0/0

2/2

Tachypnea

0/0

0/0

2/2

Urine stained abdominal fur

0/0

4/2

5/1

Impaired righting reflex

0/0

0/0

1/1

Scant faeces

0/0

0/0

1/1

Clear perinasal substance

0/0

1/1

0/0

Chromorhinorrhea

0/0

1/1

0/0

Maximum possible incidence

14/1

56/4

17/4

Maximum possible incidence = (days x rats)/number of rats examined per group
N/N = total number of observations/number of rats with observation

   

Table 3: Summary of body weight data

Rat body weight (g)

175 mg/kg bw

550 mg/kg bw

1750 mg/kg bwa

Day 1

203 ± 0.0

216.0 ± 14.4

225.8 ± 14.9

Day 2

219.0 ± 0.0

223.5 ± 22.7

229.0 ± 0.0

Day 3

216.0 ± 0.0

234.2 ± 19.5

220.0 ± 0.0

Day 4

227.0 ± 0.0

235.0 ± 19.1

234.0 ± 0.0

Day 5

228.0 ± 0.0

240.0 ± 22.4

246.0 ± 0.0

Day 6

233.0 ± 0.0

236.2 ± 19.0

254.0 ± 0.0

Day 7

241.0 ± 0.0

239.8 ± 21.4

258.0 ± 0.0

Day 8

239.0 ± 0.0

243.0 ± 25.1

255.0 ± 0.0

Day 9

241.0 ± 0.0

247.5 ± 24.6

262.0 ± 0.0

Day 10

246.0 ± 0.0

248.0 ± 22.2

262.0 ± 0.0

Day 11

261.0 ± 0.0

250.0 ± 18.8

268.0 ± 0.0

Day 12

254.0 ± 0.0

251.0 ± 17.6

272.0 ± 0.0

Day 13

263.0 ± 0.0

249.8 ± 24.0

279.0 ± 0.0

Day 14

263.0 ± 0.0

252.5 ± 24.0

276.0 ± 0.0

Mean ± SD
a= Excludes values for rats found dead.

 

Table 4: Summary of feed consumption data

Feed consumption (g/day)

175 mg/kg bw

550 mg/kg bw

1750 mg/kg bwa

Day 1-2

17.0 ± 0.0

11.8 ± 3.9

1.0 ± 0.0

Day 2-3

17.0 ± 0.0

19.8 ± 3.5

1.0 ± 0.0

Day 3-4

17.0 ± 0.0

18.5 ± 5.4

12.0 ± 0.0

Day 4-5

18.0 ± 0.0

17.7 ± 1.2

17.0 ± 0.0

Day 5-6

17.0 ± 0.0

18.0 ± 5.0

20.0 ± 0.0

Day 6-7

20.0 ± 0.0

20.5 ± 1.7

24.0 ± 0.0

Day 7-8

19.0 ± 0.0

19.2 ± 5.1

22.0 ± 0.0

Day 8-9

22.0 ± 0.0

19.2 ± 4.4

22.0 ± 0.0

Day 9-10

17.0 ± 0.0

21.5 ± 1.3

26.0 ± 0.0

Day 10-11

24.0 ± 0.0

19.0 ± 1.6

24.0 ± 0.0

Day 11-12

16.0 ± 0.0

20.5 ± 3.3

24.0 ± 0.0

Day 12-13

17.0 ± 0.0

18.5 ± 3.1

25.0 ± 0.0

Day 13-14

20.0 ± 0.0

18.2 ± 3.3

21.0 ± 0.0

Day 1-14

18.5 ± 0.0

18.7 ± 2.2

18.4 ± 0.0

Mean ± SD
a= Excludes values for rats found dead.

Interpretation of results:
other: CLP/EU GHS Category 4 (H302) according to Regulation (EC) No 1272/2008
Conclusions:
CLP: Acute tox 4, H 302
Executive summary:

Based on this study, the LD50 for ethyl phenols was determined to be 980.62 mg/kg bw. Mortality occurred in three of the four rats given the highest dose of 1750 mg/kg bw. Adverse clinical signs were observed at doses of 550 and 1750 mg/kg bw. A single dose of 175 mg/kg bw had no observable effect during the study.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no
Species:
rat
Strain:
other: Crl:CD(SD)IGS BR VAF/Plus
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina, USA
- Age at study initiation: 62 days (at arrival)
- Weight at study initiation: 198 - 217 g (on day after arrival)
- Fasting period before study: Fasted on the night before dosage administration, with feed returned to the animals folloing the 4 h clinical observation.
- Housing: Individually housed in stainless steel wire-bottomed cages.
- Diet (e.g. ad libitum): Certified Rodent Diet #5002 (PMI Nutrition International, Inc., St. Louis, Missouri, USA)
- Water (e.g. ad libitum): Local water, passed through a reverse osmosis membrane, available ad libitum, via automatic watering system.
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 64 - 79°F (18 - 26°C)
- Humidity (%): 30 - 70%
- Air changes (per hr): Positive airflow, max. 10 changes per hour, HEPA filtered
- Photoperiod (hrs dark / hrs light): 12 h dark / 12 h light

IN-LIFE DATES: From: 01 March 2004 To: 25 March 2004
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 35 mg/mL vehicle, 110 mg/mL vehicle, 350 mg/mL vehicle
- Amount of vehicle (if gavage): 5 mL/kg
- Justification for choice of vehicle: Not stated, guideline vehicle substance.
- Lot/batch no. (if required):
- Purity:

MAXIMUM DOSE VOLUME APPLIED: 5 mL/kg
Doses:
175, 550 and 1750 mg/kg bw
No. of animals per sex per dose:
All females, 1 rat for 175 mg/kg bw, 4 rats for 550 mg/kg bw and 4 rats for 1750 mg/kg bw
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Pre-dose, at least once in the 30 mins after dosage, at 30 mins, 60 mins, 2 h and 4 h and then daily thereafter for observations. Body weights were recorded weekly during acclimation, daily during the dosing and observation period and at sacrifice.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, feed consumption
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
980.62 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Calculated from log 10 values.
Sex:
female
Dose descriptor:
other: NOEL
Effect level:
ca. 175 mg/kg bw
Based on:
other: Adverse clinical signs at 550 mg/kg bw
Mortality:
One rat in the 550 mg/kg bw dose group was sacrificed in a moribund condition, as were two rats in the 1750 mg/kg bw dose group. Two rats in the 1750 mg/kg bw dose group were found dead. These deaths were considered to be treatment related and adverse clinical signs were observed.
Clinical signs:
Clinical signs which were determined to be dose related were as follows. The rat sacrificed in the 550 mg/kg bw group displayed a hunched posture, gasping and scant faeces, it lost body weight and was sacrificed in a moribund condition. One rat in the 1750 mg/kg bw group displayed a lost righting reflex, decreased motor activity, twitches, ptosis and lacrimation and was then sacrificed in a moribund condition 41 minutes after dose administration. One rat was sacrificed in a moribund condition after displaying a lost righting reflex, decreased motor activity, ataxia, impaired righting reflex, twitches, ptosis and lacrimation. The third rat was found dead but a lost righting reflex, decreased motor activity, ataxia, impaired righting reflex, twitches and lacrimation had all been observed. The fourth rat was also found dead afte displaying a lost righting reflex, decreased motor activity, twitches, ptosis, lacrimation, lost proprioceptive positioning, prostrate, excess salivation, gasping and hyperpnea.
Body weight:
All surviving rats in the 175 and 550 mg/kg bw groups gained weight during the study after dosing. Body weight changes were reduced in the 550 mg/kg bw group compared to the rat in the 175 mg/kg bw group.
Gross pathology:
Persisitent clinical observations were confirmed at necropsy. No gross lesions were found.
Other findings:
Feed consumption, both absolute (g/day) and relative (g/kg bw/day) were reduced in the 550 mg/kg bw group compared to the 175 mg/kg bw dose group.

Mortality or moribundity occurred in one of four rats administered with 550 mg/kg bw and all four rats dosed with 1750 mg/kg bw of mixed xylenols. Adverse clinial signs were observed at doses of 550 and 1750 mg/kg bw. Clinical signs included: a hunched posture, gasping and scant faeces when dosed with 550 mg/kg bw and lost righting reflex, decreased motor activity, twitches, ptosis, lacrimation, ataxia, impaired righting reflex, lost proprioceptive positioning, prostrate, excess salivation, gasping and hyperpnea in the 1750 mg/kg bw dose group. Persisitent clinical observations were confirmed at necropsy. No gross lesions were found.

Body weight changes were reduced in the 550 mg/kg bw group compared to the rat in the 175 mg/kg bw group. Feed consumption, both absolute (g/day) and relative (g/kg bw/day) were reduced in the 550 mg/kg bw group compared to the 175 mg/kg bw dose group.

Table 1: Mortality results of the up and down procedure with mixed xylenols

Step

Dose (mg/kg bw)

Response

Include

Log10 dose

1

175

O

No

-

2

550

O

Yes

2.740

3

1750

X (MS)

Yes

3.243

4

550

X (MS)

Yes

2.740

5

1750

X (MS)

Yes

3.243

6

550

O

Yes

2.740

7

1750

X

Yes

3.243

8

550

O

Yes

2.740

9

1750

X

Yes

3.243

Total

23.932

O = alive, X = dead
Sum of log10 doses/# of eligible rats: 23.932/8 = 2.9915, antilog of 2.9915 = 980.62 mg/kg bw = LD50

Table 2: Summary of observations of adverse effects during study

Observation

175 mg/kg bw

550 mg/kg b w

1750 mg/kg bw

Mortality (found dead)

0

0

2

Mortality (moribund sacrifice)

0

1

2

Lost righting reflex

0/0

0/0

4/4

Decreased motor activity

0/0

0/0

4/4

Twitches

0/0

0/0

4/4

Lacrimation

0/0

0/0

4/4

Ptosis

0/0

0/0

3/3

Ataxia

0/0

2/2

2/2

Impaired righting reflex

0/0

0/0

2/2

Gasping

0/0

1/1

1/1

Lost proprioceptive positioning

0/0

0/0

1/1

Prostrate

0/0

0/0

1/1

Excess salivation

0/0

0/0

1/1

Hyperpnea

0/0

0/0

1/1

Hunched posture

0/0

2/2

0/0

Scant faeces

0/0

1/1

0/0

Maximum possible incidence

14/1

45/4

5/4

Maximum possible incidence = (days x rats)/number of rats examined per group
N/N = total number of observations/number of rats with observation

Table 3: Summary of body weight data

Rat body weight (g)

175 mg/kg bw

550 mg/kg bw

1750 mg/kg bwa

Day 1

209.0 ± 0.0

215.2 ± 14.2

218.5 ± 15.9

Day 2

224.0 ± 0.0

218.5 ± 12.6

-

Day 3

228.0 ± 0.0

225.0 ± 16.8

-

Day 4

228.0 ± 0.0

232.3 ± 17.8

-

Day 5

239.0 ± 0.0

234.3 ± 22.8

-

Day 6

238.0 ± 0.0

237.0 ± 25.6

-

Day 7

241.0 ± 0.0

233.7 ± 26.8

-

Day 8

248.0 ± 0.0

237.7 ± 25.2

-

Day 9

246.0 ± 0.0

239.3 ± 22.5

-

Day 10

252.0 ± 0.0

243.3 ± 18.2

-

Day 11

255.0 ± 0.0

244.3 ± 25.1

-

Day 12

260.0 ± 0.0

245.3 ± 26.4

-

Day 13

260.0 ± 0.0

244.7 ± 25.8

-

Day 14

262.0 ± 0.0

246.0 ± 27.9

-

Mean ± SD
a= Excludes values for rats found dead.

 

Table 4: Summary of feed consumption data

Feed consumption (g/day)

175 mg/kg bw

550 mg/kg bw

1750 mg/kg bwa

Day 1-2

18.0 ± 0.0

11.3 ± 6.0

-

Day 2-3

23.0 ± 0.0

16.8 ± 7.3

-

Day 3-4

16.0 ± 0.0

16.3 ± 2.5

-

Day 4-5

29.0 ± 0.0

19.0 ± 6.1

-

Day 5-6

29.0 ± 0.0

18.7 ± 6.4

-

Day 6-7

20.0 ± 0.0

16.7 ± 2.1

-

Day 7-8

15.0 ± 0.0

19.3 ± 1.5

-

Day 8-9

21.0 ± 0.0

16.0 ± 4.4

-

Day 9-10

19.0 ± 0.0

19.0 ± 0.0

-

Day 10-11

18.0 ± 0.0

19.7 ± 2.5

-

Day 11-12

13.0 ± 0.0

17.3 ± 4.7

-

Day 12-13

20.0 ± 0.0

18.7 ± 2.5

-

Day 13-14

18.0 ± 0.0

17.0 ± 2.6

-

Day 1-14

19.2 ± 0.0

17.9 ± 1.9

-

Mean ± SD
a= Excludes values for rats found dead.

 

Interpretation of results:
other: CLP/EU GHS Category 4 (H302) according to Regulation (EC) No 1272/2008
Conclusions:
CLP: Acute tox 4, H 302
Executive summary:

Based on this study, the LD50 for mixed xylenols was determined to be 980.62 mg/kg bw. Mortality occurred in three of the four rats given the highest dose of 1750 mg/kg. Adverse clinical signs were observed at doses of 550 and 1750 mg/kg. A single dose of 175 mg/kg had no observable effect during the study.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Key result
Sex:
male
Dose descriptor:
LD50
Remarks:
rat
Effect level:
121 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Source, CAS 95-48-7, o-cresol, IBTL, 1969

In the result table above the most critical value of the weight of evidence approach is given. In the following, the results are shown for the other source substances of this weight of evidence approach:

Source CAS 106 -44 -5: p-cresol: LD50 (male, rat) = 207 mg/kg bw (95% CL: >=172 <= 250); IBTL, 1969

Source CAS 108 -39 -4: m-cresol: LD50 (male, rat) = ca. 242 mg/kg bw (95% CL: >=190 <= 308); IBTL, 1969

Source mixed xylenols: LD50 (female, rat) = 980.62 mg/kg bw; Merisol, 2005

Source mixed ethylphenols: LD50 (female, rat) = 980.62 mg/kg bw; Merisol, 2005

Interpretation of results:
other: CLP/EU GHS Category 3 (H301) according to Regulation (EC) No 1272/2008
Conclusions:
Based on all available information (weight-of-evidence), following an analogue read-across approach and in the absence of data on acute oral toxicity of Tar acids, Xylenol fraction (CAS 84989-06-0), Tar acids, Xylenol fraction (CAS 84989-06-0) is classified for Acute oral toxicity (Cat. 3, H301) as a worst case.
Executive summary:

Studies on mixed ethyl phenols and mixed xylenols resulted in a LD50 of 989.62 mg/kg bw. For the three cresol isomers the LD50 values were between 121 and 242 mg/kg bw. Thus, the cresol isomers seem to have a more toxic potential regarding acute oral toxicity than mixed ethyl phenols and mixed xylenols. However, as there are no acute oral toxicity data available for Tar acids, Xylenol fraction (CAS 84989-06-0) a worst-case approach was conducted taking into account all available data on the source substances and Tar acids, Xylenol fraction (CAS 84989-06-0) was therefore classified in Cat. 3 (H301) for acute oral toxicity according to Regulation (EC) No 1272/2008.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
121 mg/kg bw
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1 or 2) studies from reference substances with similar structure. Read-across is justified based on data on the constituents of Tar acids, xylenol fraction (CAS 84989-06-0) (refer to endpoint discussion for further details). Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: no guideline study; 1 hr exposure time; non-GLP
Qualifier:
no guideline followed
Principles of method if other than guideline:
Exposure to the substance for 1 hr, room temperature, total air flow: 10.0 lpm (no further information), up to 14 d post exposure observation, gross necropsy
GLP compliance:
no
Test type:
traditional method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
no further data
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
air
Details on inhalation exposure:
no further data
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
ca. 1 h
Concentrations:
0.71 mg/L
No. of animals per sex per dose:
6 male rats
Control animals:
no
Details on study design:
no further data
Statistics:
no data
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
> 0.71 mg/L air
Based on:
test mat.
Exp. duration:
1 h
Mortality:
no
Clinical signs:
no
Body weight:
initial mean body weight: 218 g, terminal mean body weight: 270 g
Gross pathology:
no findings
Other findings:
no further data
Interpretation of results:
study cannot be used for classification
Conclusions:
LC50 > 0.71 mg/L for 1 h
Executive summary:

Following exposure of rats against 0.71 mg/L p-cresol for 1 hour, no rat died and no clinical findings were reported.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: no information about strain used, exposure time: 1 hr, only one concentration
Qualifier:
no guideline followed
Principles of method if other than guideline:
6 rats exposed to 0.71 mg/L for 1 hr, room temperature, up to 14 d post exposure observation, gross necropsy
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 212 g

ENVIRONMENTAL CONDITIONS
- Temperature (°C): room temperature
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
air
Details on inhalation exposure:
CONDITIONS:
Room temperature
Total air flow: 10.0 lpm
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
ca. 1 h
Concentrations:
0.71 mg/L
No. of animals per sex per dose:
6
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations daily
- weighing: at the end of the study
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, gross pathology
Statistics:
no data
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
> 0.71 mg/L air
Based on:
test mat.
Exp. duration:
1 h
Mortality:
0/6
Clinical signs:
none mentioned
Body weight:
mean weight: initial: 212 g; at termination of the study: 256 g
Gross pathology:
no significant findings
Other findings:
none
Interpretation of results:
study cannot be used for classification
Conclusions:
LC50 > 0.71 mg/L for 1h
Executive summary:

No mortality occurred following the exposure of 6 rats to 0.71 mg/L for 1 hr and within the 14 day observation period. Clinical signs or findings following sacrifice were not reported.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Secondary citation from peer-reviewed data source. No detail of exposure duration.
Principles of method if other than guideline:
aerosol-exposure; no further data
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
no further data
Type of inhalation exposure:
not specified
Vehicle:
not specified
Details on inhalation exposure:
no further data
Concentrations:
no data
Key result
Sex:
not specified
Dose descriptor:
LC50
Effect level:
58 mg/m³ air
Based on:
test mat.
Mortality:
50% of the rats in test
Clinical signs:
irritation of the mucous membranes, neuromuscular excitation, and convulsions
at very high doses (not further specified): haematuria
Body weight:
no data
Gross pathology:
no data
Interpretation of results:
study cannot be used for classification
Conclusions:
LC50 value = 58 mg/m³
Executive summary:

In rats, the LC50 value of 58 mg/m³ resulted from exposure against m-cresol aerosols (exposure time not mentioned). Clinical signs reported included irritation of the mucous membranes, neuromuscular excitation and convulsions.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Study based on accepted scientific principles, of limited use for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Inhalation hazard test: Exposure to an atmosphere enriched with the test substance at ambient temperature
GLP compliance:
no
Test type:
other: inhalation risk test
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. A. Ivanovas, Kisslegg/Allgäu/Germany
- Age at study initiation: no data
- Weight at study initiation: 115 - 140 g (male, female)
- Fasting period before study: 16
- Housing: 5 per cage
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Air-conditioned room
- Temperature (°C): 22 +- 1 °C
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass tube
- Exposure chamber: 150 mm (diameter) x 1000 mm (length)
- Method of holding animals in test chamber: in a segment of the inhalation tube
- Source and rate of air: micro-filtered pressure air
- Method of conditioning air: passed through a layer of 5 cm finely granulated test substance
- air rate: 480 L/h (L/min)
- Treatment of exhaust air: exhaust hood
- Temperature, humidity, pressure in air chamber: 24 °C
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
7 h
Concentrations:
no data, test-substance enriched air (24 °C): < saturation concentration (Cs)
Cs = ~ 0.13 mg/L (based on a vapour pressure of 0.027 hPa at 25 °C and the molecular mass of 122 g/mol)
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: 1x/day
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
not applicable
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 0.07 mg/L air
Based on:
test mat.
Exp. duration:
7 h
Remarks on result:
other: estimated air concentration (as gas) based on saturation (~ 1.3 mg/L), assuming 50 % air saturation under test conditions.
Mortality:
none
Clinical signs:
no particular observations
Body weight:
normal
Gross pathology:
no particular findings
Interpretation of results:
study cannot be used for classification
Conclusions:
LC 50 > 0.07 mg/L following 7 h exposure
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: only one dose, individual animal data not shown, exposure period: 1 hour
Qualifier:
no guideline followed
Principles of method if other than guideline:
room temperature, total air flow: 10.0 lpm (no further information) observation for clinical signs and mortality, gross autopsy
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
no further data
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
other: air
Details on inhalation exposure:
no further data
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
1 h
Concentrations:
1.22 mg/L
No. of animals per sex per dose:
6 male rats
Control animals:
not specified
Details on study design:
no further data
Statistics:
no data
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
> 1.22 mg/L air
Based on:
test mat.
Exp. duration:
1 h
Mortality:
no
Clinical signs:
generalized inactivity, lacrimation; onset: 15 - 30 minutes; recovery at treatment day
Body weight:
initial mean body weight: 197 g; terminal mean body weight: 250 g
Gross pathology:
no significant findings
Other findings:
no further details

no further details

Interpretation of results:
study cannot be used for classification
Conclusions:
LC50 > 122 mg/L/1h air
Executive summary:

Exposure of male rats to the test substance for 1 hour and postexposure observation for clinical signs and mortality resulted in no mortality, but generalized inactivity: LC50 > 1.22 mg/L/1h air.

Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Key result
Sex:
male
Dose descriptor:
LC50
Remarks:
rat
Effect level:
> 1.22 mg/L air
Based on:
test mat.
Exp. duration:
1 h
Remarks on result:
other: Source, CAS 95-48-7, o-cresol, IBTL, 1969

In the result table above the most critical value of the weight of evidence approach is given. In the following, the results are shown for the other source substances of this weight of evidence approach:

Source CAS 106 -44 -5: p-cresol: LC50 (male, rat) > 0.71 mg/L air (1 h exposure duration); IBTL, 1969

Source CAS 108 -39 -4: m-cresol: LC50 (male, rat) > 0.71 mg/L air (1 h exposure duration); IBTL, 1969

Source CAS 108 -39 -4: m-cresol: LC50 (sex not specified, rat) 58.0 mg/m³ air (exposure duration not specified); Pereima, 1975

Source CAS 108 -68 -9: 3,5 -xylenols: LC50 (male/female, rat) > 0.07 mg/L air; (7 h exposure duration), estimated air concentration (as gas) base on saturation (~ 1.3 mg/L), assuming 50% air saturation under test conditions; (Rütgers, 1981)

Interpretation of results:
other: overall data base is not sufficient for a final conclusion
Conclusions:
Based on all available information (weight-of-evidence) and following an analogue read-across approach the data does not allow a final conclusion on acute inhalation toxicity. Further testing is, however, not required, because Tar acids, Xylenol fraction (CAS 84989-06-0) is evaluated as corrosive in a worst-case approach and classified / labelled accordingly. This is in accordance with the specific rules (Column 2) of Annex VIII No. 8.5 of Regulation (EC) No. 1907/2006 (REACH): acute toxicity studies do not generally need to be conducted if the substance is classified as corrosive to the skin.
Executive summary:

Studies on cresol isomers and 3,5-xylenol are available, but the quality of the data does not allow a final conclusion on acute inhalation toxicity. Further testing is, however, not required, because Tar acids, Xylenol fraction (CAS 84989-06-0) is evaluated as corrosive in a worst-case approach and classified / labelled accordingly. This is in accordance with the specific rules (Column 2) of Annex VIII No. 8.5 of Regulation (EC) No. 1907/2006 (REACH): acute toxicity studies do not generally need to be conducted if the substance is classified as corrosive to the skin.

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Data base regarding acute inhalation toxicity is very limited and does not allow a final conclusion. Further testing is, however, not required, because Tar acids, Xylenol fraction (CAS 84989-06-0) is evaluated as corrosive, classified for acute dermal toxicity (Acute Tox. 3, H311) and is a crystalline solid. Therefore, no further testing is warranted according to REACH Regulation (EC) No 1907/2006, Annex VIII, Column 2.

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: no information about strain used, no information on GLP, duration time not stated
Qualifier:
no guideline followed
Principles of method if other than guideline:
5 rabbits/dose, 4 doses, exposure time not mentioned, up to 14 day observation time, gross autopsy
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
no further data
Vehicle:
other: none
Details on dermal exposure:
no further data
Duration of exposure:
no data
Doses:
215, 316, 464, 681 mg/kg bw
No. of animals per sex per dose:
5 rabbits per dose
Control animals:
no
Details on study design:
no further data
Statistics:
yes, but method not mentioned
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
ca. 301 mg/kg bw
Based on:
test mat.
95% CL:
>= 213 - <= 426
Mortality:
215 mg/kg bw: 1/5; 316 mg/kg bw: 3/5; 464 mg/Kg bw: 4/5; 681 mg/kg bw: 5/5
Clinical signs:
signs of intoxication from 4 - 12 hrs post appl.: tremor, salivation sedation, recovery occurred within 3 days post application
Body weight:
initial mean body weight ranged from 2.5 - 2.7 kg; mean terminal body weight of rabbits dosed with 215 mg/kg bw: 2.3 kg (no further data given)
Gross pathology:
gross autopsy: survivors: no significant findings; decedents: inflammation of kidneys
Other findings:
dermal irritation: severe subdermal hemorrhaging, severe erythema
Interpretation of results:
other: CLP/EU GHS Category 3 (H311) according to Regulation (EC) No 1272/2008
Conclusions:
CLP: Acute tox 3, H 311
Executive summary:

To determine LD-50 value, rabbits received dermal application of 215 - 681 mg/kg bw undiluted p-cresol and were observed for sclinical signs of toxicity and mortality for up to 14 days: LD50 was determined to be 301 mg/kg bw. As signs of intoxication tremor, salivation, sedation were noted; the treated skin showed severe erythema and severe subdermal hemorrhaging.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: no information about strain used, statistical evaluation not given, no guideline followed
Qualifier:
no guideline followed
Principles of method if other than guideline:
5 rabbits/dose, 4 doses, exposure time not mentioned, up to 14 days post exposure observation time
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.29 - 2.67 kg
Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
no further data
Duration of exposure:
no data
Doses:
1000, 1470, 2150, 3160 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors and decedents performed: yes
- Other examinations performed: clinical signs
Statistics:
yes, method not given
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
2 050 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 590 - <= 2 650
Mortality:
1000 mg/kg bw: 0/5
1470 mg/kg bw: 0/5
2150 mg/kg bw: 4/5
3160 mg/kg bw: 4/5
Clinical signs:
signs of intoxication from 4 hrs up to 12 hrs p.a.:
lacrimation, salivation, hypersensitivity, convulsion, hypoactivity; dermal irritation: severely burned, severe oedema
Body weight:
terminal body weight: no data
Gross pathology:
survivors: no significant finding; gross necropsy-decedents: hyperemia of lungs and kidneys
Other findings:
no data

Table 1: Mortality and clinical symptoms

Dosage

mg/kg bw

onset of sympt

4-12 hrs

mortality

Mortality

cumulative

12-24 hrs

day 3

1000

0/5

1470

0/5

2150

S

4/5

4/5

3160

S

4/5

4/5

 

S = signs of intoxication from 4 hrs up to 12 hrs p.a.:

lacrimation, salivation, hypersensitivity, convulsion, hypoactivity;
dermal irritation: severely burned, severe oedema; gross necropsy-survivors: no significant finding, gross necropsy-decedents: hyperemia of lungs and kidneys

Interpretation of results:
other: CLP/EU GHS criteria are not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
CLP: not classified
Executive summary:

Application of test substance to the skin of rabbits and an exposure observation time for 14 days yielded a LD50 of 2050 mg/kg bw and severe irritational effects.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. A. Ivanovas, Kisslegg/Allgäu/Germany
- Age at study initiation: no data
- Weight at study initiation: 210 - 235 g (male); 200 - 230 g (female)
- Fasting period before study: no
- Housing: 1 per cage
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Air-conditioned room
- Temperature (°C): 22 +- 1 °C
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
polyethylene glycol
Details on dermal exposure:
TEST SITE
- Area of exposure: 5 cm x 7.5 cm, shaved, intact skin
- Administration: Dosing in dissolved form by syringe (at elevated temperature to prevent precipitation)
- Type of wrap: thin aluminum foil covering the treated area and adhesive bandage ("Elastoplast") round the trunk


REMOVAL OF TEST SUBSTANCE
- Washing (if done): lukewarm water
- Time after start of exposure: 24 h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 3 mL/kg bw of test solution (highest test volume technically achievable on the skin area)
- Concentration (if solution): 80% in PEG 300
- Constant volume or concentration used: yes
- For solid: dissolved in PEG at 50 °C, at lower temperature precipitation
Duration of exposure:
24 h

Doses:
2400 mg/kg bw (3,5-xylenol)
[Note: In report 2.4 mL/kg is mentioned, but not conclusive as 80% solution of the solid test substance in PEG should relate to w/v. 3 mL solution/kg were applied => 80% (w/v) = 2.4 g/kg bw.]
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: several-fold on the day of treatment, thereafter daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
not applicable
Sex:
male/female
Dose descriptor:
LD0
Effect level:
2 400 mg/kg bw
Based on:
test mat.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 400 mg/kg bw
Based on:
test mat.
Mortality:
none
Clinical signs:
no particular observations
Body weight:
no significant differences from the control groups
Gross pathology:
no skin reactions (effects scores = 0) ; no particular findings at organs
Other findings:
none

No clinical signs of toxicity reported up to 2400 mg/kg

Interpretation of results:
other: CLP / GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008.
Conclusions:
CLP: not classified
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: individual animal data not shown, no information about strain used, statistical evaluation not given, no guideline followed
Qualifier:
no guideline followed
Principles of method if other than guideline:
5 rabbits/dose, exposure period not given, observation up to 14 days, gross autopsy
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
no further data
Type of coverage:
not specified
Vehicle:
other: undiluted
Details on dermal exposure:
no further data
Duration of exposure:
no data
Doses:
681, 1000, 1470, 2150 mg/kg bw
No. of animals per sex per dose:
5 rabbits/dose
Control animals:
not specified
Details on study design:
no further data
Statistics:
yes, but method not mentioned
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
1 380 mg/kg bw
Based on:
test mat.
95% CL:
>= 841 - <= 2 260
Mortality:
681 mg/kg bw: 1/5
1000 mg/kg bw: 2/5
1470 mg/kg bw: 2/5
2150 mg/kg bw: 4/5
Clinical signs:
Hypoactivity salivation, tremors; dermal irritation: severe erythema
Body weight:
initial bw 2.44 - 2.61 kg; terminal bw not given
Gross pathology:
gross autopsy: survivors: no significant findings; decedents: hyperemia of the liver and lungs
Other findings:
no further details
Interpretation of results:
other: CLP/EU GHS Category 4 (H312) according to Regulation (EC) No 1272/2008
Conclusions:
CLP: Acute tox 4, H 312
Executive summary:

Dermal application of the testsubstance to the skin of rabbits resulted in a LD50 value of 1380 mg/kg bw (Industrial Biotest Laboratories 1969).

Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Key result
Sex:
not specified
Dose descriptor:
LD50
Remarks:
rabbit
Effect level:
ca. 301 mg/kg bw
Based on:
test mat.
95% CL:
>= 213 - <= 426
Remarks on result:
other: Source, CAS 106-44-5, p-cresol, IBTL, 1969

In the result table above the most critical value of the weight of evidence approach is given. In the following, the results are shown for the other source substances of this weight of evidence approach:

Source CAS 95 -48 -7: o-cresol: LD50 (sex unspecified, rabbit) = 1380 mg/kg bw (95% CL: >= 841 <= 2260); IBTL, 1969

Source CAS 108 -39 -4: m-cresol: LD50 (sex not specified, rabbit) > 2050 mg/kg bw; IBTL, 1969

Source CAS 108 -68 -9: 3,5-xylenols: LD50 (male/female, rat) >2400 mg/kg bw; Rütgers, 1981

Interpretation of results:
other: CLP/EU GHS Category 3 (H311) according to Regulation (EC) No 1272/2008
Conclusions:
Based on all available information (weight-of-evidence), following an analogue read-across approach and in the absence of data regarding acute dermal toxicity of Tar acids, Xylenol fraction (CAS 84989-06-0), Tar acids, Xylenol fraction (CAS 84989-06-0) is classified for Acute dermal toxicity (Cat. 3, H311) as a worst case.
Executive summary:

The acute dermal toxicty study on 3,5-xylenol resulted in a LD50 of > 2400 mg/kg bw for male and female rats. For the three cresol isomers the LD50 values were between 301 and 2050 mg/kg bw for rabbits. Thus, the cresol isomers seem to have a more toxic potential regarding acute dermal toxicity than 3,5-xylenol. However, as there are no acute dermal toxicity data available for Tar acids, Xylenol fraction (CAS 84989-06-0) a worst-case approach was conducted taking into account all available data on the source substances and Tar acids, Xylenol fraction (CAS 84989-06-0) was therefore classified in Cat. 3 (H311) for acute dermal toxicity according to Regulation (EC) No 1272/2008.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
301 mg/kg bw
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure. Read-across is justified based on data on the constituents of Tar acids, xylenol fraction (CAS 84989-06-0) (refer to endpoint discussion for further details). Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Justification for read-across

There are no data for acute toxicity available for Tar acids, Xylenol fraction (CAS 84989-06-0). In order to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.5, read-across from appropriate substances is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5.

According to Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met”. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across) “to avoid the need to test every substance for every endpoint”.

Tar acids, Xylenol fraction (CAS 84989-06-0) is an UVCB substance comprised of the main constituents xylenols (all isomers in total > 60%; 2,4- and 2,5-xylenol > 40%), ethyl phenols (< 30%) and cresols (< 25%). The read-across approach is therefore based on the main constituents of Tar acids, Xylenol fraction (CAS 84989-06-0), given common functional groups, common precursors and the likelihood of common breakdown products via biological processes. For further details on the read-across approach, please refer to the analogue justification in section 13 of the technical dossier.

For acute oral toxicity read-across from reliable data on the analogue substances mixed xylenols, mixed ethyl phenols as well as to the cresol isomers (m- (CAS 108-39-4), p- (CAS 106-44 5) and o-cresol (CAS 95-48-7)) was conducted. For acute inhalation toxicity data are available on the cresol isomers (m- (CAS 108-39-4), p- (CAS 106-44 5) and o-cresol (CAS 95-48-7)) and on the analogue substance 3,5-xylenol (CAS 108-68-9). Nevertheless, the data base is very limited and does not allow a final conclusion. Further testing is, however, not required, because Tar acids, Xylenol fraction (CAS 84989-06-0) is evaluated as corrosive in a worst-case approach and classified / labelled accordingly. This is in accordance with the specific rules (Column 2) of Annex VIII No. 8.5 of Regulation (EC) No. 1907/2006 (REACH): acute toxicity studies do not generally need to be conducted if the substance is classified as corrosive to the skin. For acute dermal toxicity read-across to reliable data on the cresol isomers (m- (CAS 108-39-4), p- (CAS 106-44 5) and o-cresol (CAS 95-48-7)) and on the analogue substance 3,5-xylenol (CAS 108-68-9) was conducted.

Acute oral toxicity

Mixed xylenols (analytical grade)

An acute oral toxicity study was performed with mixed xylenols (analytical grade) according to OECD 425 and under GLP (Merisol, 2005a). The oral up and down procedure was performed on female rats with doses of 175, 550 and 1750 mg/kg bw (via gavage, in corn oil). All together 1 rat received 175 mg/kg bw, 4 rats received 550 and 1750 mg/kg bw, respectively, until the criteria for an LD50 determination were fulfilled. One rat in the 550 mg/kg bw dose group was sacrificed in a moribund condition, as were two rats in the 1750 mg/kg bw dose group. Two rats in the 1750 mg/kg bw dose group were found dead. These deaths were considered to be treatment-related and adverse clinical signs were observed. Clinical signs which were determined to be dose-related were as follows: The rat sacrificed in the 550 mg/kg bw group displayed a hunched posture, gasping and scant faeces, it lost body weight and was sacrificed in a moribund condition. One rat in the 1750 mg/kg bw group displayed a lost righting reflex, decreased motor activity, twitches, ptosis and lacrimation and was then sacrificed in a moribund condition 41 minutes after dose administration. One rat was sacrificed in a moribund condition after displaying a lost righting reflex, decreased motor activity, ataxia, impaired righting reflex, twitches, ptosis and lacrimation. The third rat was found dead but a lost righting reflex, decreased motor activity, ataxia, impaired righting reflex, twitches and lacrimation had all been observed. The fourth rat was also found dead after displaying a lost righting reflex, decreased motor activity, twitches, ptosis, lacrimation, lost proprioceptive positioning, prostrate, excess salivation, gasping and hyperpnea. All surviving rats in the 175 and 550 mg/kg bw groups gained weight during the study after dosing. Body weight changes were reduced in the 550 mg/kg bw group compared to the rat in the 175 mg/kg bw group. Persistent clinical observations were confirmed at necropsy. No gross lesions were found. Food consumption, both absolute (g/day) and relative (g/kg bw/day) were reduced in the 550 mg/kg bw group compared to the 175 mg/kg bw dose group. Based on this study, the LD50 for mixed xylenols (analytical grade) was determined to be 980.62 mg/kg bw.

Mixed ethyl phenols (analytical grade)

An acute oral toxicity study was performed with mixed ethyl phenols (analytical grade) according to OECD 425 and under GLP (Merisol, 2005b). The oral up and down procedure was performed on female rats with doses of 175, 550 and 1750 mg/kg bw (via gavage, in corn oil). All together 1 rat received 175 mg/kg bw, 4 rats received 550 and 1750 mg/kg bw, respectively, until the criteria for an LD50 determination were fulfilled. Three rats died in the 1750 mg/kg bw dose group from treatment-related effects. Clinical observations which were determined to be dose-related included lacrimation, excess salivation and urine stained fur in both the 550 and 1750 mg/kg bw dose groups. Decreased motor activity, twitches, prostrate, ptosis, limited use of hind limbs, lost proprioceptive positioning, no use of both hind and forelimbs, ataxia, lost righting reflex, tachypnea, impaired righting reflex and scant faeces were observed in the 1750 mg/kg bw dose group. Body weight changes were reduced in the 550 and 1750 mg/kg bw dose groups compared to the rat in the 175 mg/kg bw dose group. However, all surviving rats gained weight after dose administration. Necropsy confirmed the clinical observations. No gross lesions were found. Food consumption values, both absolute (g/day) and relative (g/kg bw/day), showed a dose-dependent reduction on the day after dosing in the 550 and 1750 mg/kg bw dose groups. This trend continued until day 5 post-dosing, after which the values remained comparative to the 175 mg/kg bw dosed animal. Based on this study, the LD50 for mixed ethyl phenols (analytical grade) was determined to be 980.62 mg/kg bw.

o-cresol (CAS 95-48-7)

o-cresol (CAS 95-48-7) was tested for acute oral toxicity similarly to OECD 401 (IBTL, 1969a). Five male rats received single oral gavage doses of the test substance at dose levels of 68, 100, 147 and 215 mg/kg bw. Mortality was observed in the 100 mg/kg bw test group (2/5), in the 147 mg/kg bw test group (3/5) and in the 215 mg/kg bw test group (5/5). All animals showed signs of intoxication including hypoactivity, tremor, convulsions, salivation, dyspnea and prostration within 4 hours post dosing. At autopsy, survivors showed no significant findings, decedents showed hemorrhage of gastrointestinal tract, hyperemia of liver, kidneys and lungs. The LD50 was determined to be 121 mg/kg bw.

p-cresol (CAS 106-44-5)

p-cresol (CAS 106-44-5) was tested for acute oral toxicity similarly to OECD 401 (IBTL, 1969b). Five male rats received single oral gavage doses of the test substance at dose levels of 100, 147, 215 and 316 mg/kg bw. Mortality was observed in the 215 mg/kg bw test group (3/5) and in the 316 mg/kg bw test group (5/5). All animals showed signs of intoxication including hypoactivity, tremors, lacrimation, dyspnea, haemorrhagic rhinitis, convulsions and prostration within 4 hours post dosing. Necropsy of the rats that died revealed gastrointestinal inflammation, haemorrhage and hyperaemia of the lungs, liver and kidney. Survivors showed gastrointestinal inflammation. The LD50 was determined to be 207 mg/kg bw.

m-cresol (CAS 108-39-4)

m-cresol (CAS 108-39-4) was tested for acute oral toxicity similarly to OECD 401 (IBTL, 1969c). Five male rats received single oral gavage doses of the test substance at dose levels of 147, 215, 316 and 464 mg/kg bw. Mortality was observed in the 215 mg/kg bw test group (2/5), in the 316 mg/kg bw test group (4/5) and in the 464 mg/kg bw test group (5/5). All animals showed signs of intoxication including hypoactivity, tremors, convulsions, salivation and prostration within 4 hours post dosing. Necropsy of the rats that died revealed inflammation of the gastrointestinal tract, hyperemia of lungs, liver and kidneys. Survivors showed no significant findings. The LD50 was determined to be 242 mg/kg bw.

Conclusion:

Based on all available information (weight-of-evidence), following an analogue read-across approach and in the absence of data regarding acute oral toxicity of Tar acids, Xylenol fraction (CAS 84989-06-0), the substance is classified for acute oral toxicity (Cat. 3, H301) as a worst case.

Acute inhalation toxicity

3,5-xylenol (CAS 108-68-9)

An inhalation hazard test was conducted with 3,5-xylenol (CAS 108-68-9; Rütgers, 1981a). 5 Sprague-Dawley rats per sex were exposed to an atmosphere enriched with the test substance at ambient temperature for 7 h and observed for 14 days. The estimated air concentration (as gas) based on saturation (~ 1.3 mg/L) is 0.07 mg/L air, assuming 50% air saturation under test conditions. No rat died and no particular observations were noted.

o-cresol (CAS 95-48-7)

Inhalation exposure of six male rats to o-cresol (CAS 95-48-7; 1.22 mg/L) for 1 h did not result in mortality, but generalised inactivity and lacrimation (IBTL, 1969a). There were no significant findings during necropsy. No further data were available.

p-cresol (CAS 106-44-5)

Inhalation exposure of six male rats to p-cresol (CAS 106-44-5; 0.71 mg/L) for 1 h did not result in mortality and any clinical signs (IBTL, 1969b). There were also no findings during necropsy. No further data were available.

m-cresol (CAS 108-39-4)

Inhalation exposure of six male rats to m-cresol (CAS 108-39-4; 0.71 mg/L) for 1 h did not result in mortality and any clinical signs (IBTL, 1969c). There were also no significant findings during necropsy. No further data were available.

In Pereima (1975), cited in WHO (1995) the LC50 in rats was reported to be 58 mg/m³ but exposure period and other relevant data were not available. Clinical signs of intoxication included irritation of mucous membranes, neuromuscular excitation and convulsions.

Conclusion:

The data base regarding acute inhalation toxicity is very limited and does not allow a final conclusion. Further testing is, however, not required, because Tar acids, Xylenol fraction (CAS 84989-06-0) is evaluated as corrosive in a worst-case approach and classified / labelled accordingly. This is in accordance with the specific rules (Column 2) of Annex VIII, No. 8.5 of Regulation (EC) No. 1907/2006 (REACH): acute toxicity studies do not generally need to be conducted if the substance is classified as corrosive to the skin. In addition, the substance is classified for acute dermal toxicity (Acute Tox. 3, H311) and is a crystalline solid. Therefore, no further testing is warranted according to thr REACH Regulation (EC) No 1907/2006, Annex VIII, Column 2.

Acute dermal toxicity

3,5-xylenol (CAS 108-68-9)

An acute dermal toxicity study was performed with 3,5-xylenols (CAS 108-68-9) similar to OECD 402, but not under GLP (Rütgers, 1981). 5 male and female Sprague Dawley rats were exposed to 2400 mg/kg bw 3,5-xylenol in polyethylene glycol to the shaved, intact skin with an occlusive dressing for 24 h. After the 24 h the exposed area was washed with lukewarm water and observed for 14 days. There were no mortalities and no particular clinical observations. The body weights were not significantly different from the control groups and there were no particular findings at necropsy. The LD50 for male and female rats was therefore determined as > 2400 mg/kg bw.

o-cresol (CAS 95-48-7)

o-cresol (CAS 95-48-7) was tested for acute dermal toxicity (IBTL, 1969a). Five rabbits/dose received single dermal doses of the test substance at dose levels of 681, 1000, 1470 and 2150 mg/kg bw. Mortality was observed in the 681 mg/kg bw test group (1/5), in the 1000 mg/kg bw test group (2/5), in the 1470 mg/kg w test group (2/5) and in the 2150 mg/kg bw test group (4/5). Animals showed signs of intoxication including hypoactivity, salivation, tremors and dermal irritation (severe erythema). At autopsy, survivors showed no significant findings, decedents showed hyperemia of liver and lungs. The LD50 was determined to be 1380 mg/kg bw.

p-cresol (CAS 106-44-5)

p-cresol (CAS 106-44-5) was tested for acute dermal toxicity (IBTL, 1969b). Five rabbits/dose received single dermal doses of the test substance at dose levels of 215, 316, 464 and 651 mg/kg bw. Mortality was observed in the 215 mg/kg bw test group (1/5), in the 316 mg/kg bw test group (3/5), in the 464 mg/kg bw test group (4/5) and in the 681 mg/kg bw test group (5/5). Animals showed signs of intoxication from 4–12 h after dosing including tremor, salivation and sedation; recovery occurred within 3 days post application. At autopsy, survivors showed no significant findings, decedents showed inflammation of the kidneys. The LD50 was determined to be 301 mg/kg bw.

m-cresol (CAS 108-39-4)

m-cresol (CAS 108-39-4) was tested for acute dermal toxicity (IBTL, 1969c). Five rabbits/dose received single dermal doses of the test substance at dose levels of 1000, 1470, 2150 and 3160 mg/kg bw. Mortality was observed in the 2150 mg/kg bw test group (4/5) and in the 3160 mg/kg bw test group (4/5). Animals showed signs of intoxication from 4 – 12 h after dosing including lacrimation, salivation, hypersensitivity, convulsion, hypoactivity and dermal irritation (severely burned, severe oedema). At autopsy, survivors showed no significant findings, decedents showed hyperemia of lungs and kidneys. The LD50 was determined to be 2050 mg/kg bw.

Conclusion:

Based on all available information (weight-of-evidence), following an analogue read-across approach and in the absence of data regarding acute dermal toxicity of Tar acids, Xylenol fraction (CAS 84989-06-0), the substance is classified for acute dermal toxicity (Cat. 3, H311) as a worst case.

Additional data:

In addition, in the public toxicological evaluation of 2,4-xylenol (CAS 105-67-9) of BG Chemie (No. 137, last updated 02/2005), the substance is to be considered as harmful based on the underlying (poorly documented) data. The authors summarise, that the oral LD50 values for the rat and the mouse are given as 3200 mg/kg bw and 809 mg/kg bw, respectively.A dermal LD50 for the rat of 1040 mg/kg bw has been reported. There is no known LC50 for inhalation exposure. Clinical signs of intoxication initially consist in CNS impairments and severe signs of irritation. Death results from respiratory arrest. In addition, 3,5-xylenol (CAS 108-68-9) was evaluated by BG Chemie (No. 139, last updated 02/2005) and is considered as harmful based on the underlying (partly very poorly documented) data. The authors summarise that oral LD50 values reported for the rat vary from 1915 to 3620 mg/kg bw. In one case, the value is given as 608 mg/kg bw. For mice, the oral LD50 values are between 477 and 620 mg/kg bw. The oral LD50 value for rabbits is given as 1313 mg/kg bw. The acute dermal toxicity has been ascertained in only one rat study (Rütgers, 1981b; available in section 7.2.3 of the technical dossier) and one rabbit study. In both cases, high single doses of 2400 and 2000 mg/kg bw, respectively, were tolerated without mortality or systemic toxicity. An inhalation hazard test in which rats were exposed to air enriched with 3,5-xylenol at 24 °C showed no treatment-related effects (Rütgers, 1981a; available in section 7.2.2 of the technical dossier). Mice exposed to 3,5-dimethylphenol at 4 mg/m³ air exhibited no marked toxic effects other than mucous membrane irritation.

References:

BG Chemie 2005: Toxicological evaluation of 2,4-Dimethylphenol (CAS No. 105-67-9), No. 137, last updated: 02/2005.

BG Chemie 2005: Toxicological evaluation of 3,5-Dimethylphenol (CAS No. 108-68-9), No. 139, last updated: 02/2005.

Justification for classification or non-classification

Based on all available information (weight-of-evidence), following an analogue read-across approach and in the absence of data on acute oral and dermal toxicity of Tar acids, Xylenol fraction (CAS 84989-06-0), Tar acids, Xylenol fraction (CAS 84989-06-0) is classified for Acute oral toxicity (Cat. 3, H301) and Acute dermal toxicity (Cat. 3, H311) as a worst case according to Regulation (EC) 1272/2008.

The data base regarding acute inhalation toxicity is very limited and does not allow a final conclusion regarding classification according to Regulation (EC) 1272/2008.