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Toxicological information

Acute Toxicity: oral

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Administrative data

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
Cross-referenceopen allclose all
Reason / purpose:
read-across source
Reference
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.

Reason / purpose:
read-across source
Reference
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.

Reason / purpose:
read-across source
Reference
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.

Reason / purpose:
read-across source
Reference
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.

Reason / purpose:
read-across source
Reference
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.

Data source

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Effect levels
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

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.