Reaction mass of 4,4'-isopropylidenediphenol and phenol

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol can be predicted by studies conducted with the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol, because the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol contains phenol (40-45%, typical concentration ca. 40%) and 4,4’-isopropylidenediphenol (BPA) (20-40%, typical concentration ca. 33%) as main constituents. Both constituents are data rich substances with distinct hazard properties, so that mainly data on the constituents have been applied to characterize the Reaction mass of phenol and 4,4’-isopropylidenediphenol. Since this is a common approach in mixture hazard assessment, is reasonable to apply it also to multi-constituent substances.
Additionally, some data from a structurally related substance (2-acetone, polymer with phenol) containing the same constituents/impurities at different concentrations are available, which are applied to characterize the environmental fate and ecotoxicity of the impurities present in the Reaction mass of phenol and 4,4’-isopropylidenediphenol.

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol are predicted to be similar to those of the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol.

Therefore, read-across from the available studies with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
please refer to justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
please refer to justification for read-across attached to Iuclid section 13

4. DATA MATRIX
please refer to justification for read-across attached to Iuclid section 13

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

read-across: supporting information

Cross-reference 2

Reason / purpose for cross-reference:

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:

The study is comparable to OECD Guideline 401 with acceptable restrictions (post exposure observation period 7 days, no necropsy and body weight data; unusual oral application). Phenol is a constituent of the reaction mass so that phenol hazard data are applied in the hazard assessment.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

(post exposure observation period 7 days, no necropsy)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Source Wistar Institute but reared in conducting laboratory; food and water ad libitum.
No further data.

Route of administration:

oral: gavage

Details on oral exposure:

Test solution injected directly by a syringe into the oesophagus using a blunt hypodermic needle traversing the esophagus if the volume is <= 1ml; presumably gavage used for higher volume; post exposure observation period not clearly stated but presumably 7 days; different amounts of aqueous preparations containing 2, 5, 10 and 20% of phenol were administered to 5-15 rats per dose group (equal numbers of males and females).

Doses:

300-800 mg/kg bw (see Table below)

No. of animals per sex per dose:

5-15 (equal number of males and females in each group); see also Table below.

Control animals:

no

Details on study design:

Further details see Table below.

Statistics:

No data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

530 mg/kg bw

Remarks on result:

other: 2 & 5% solution

Sex:

male/female

Dose descriptor:

LD50

Effect level:

540 mg/kg bw

Remarks on result:

other: 10% solution

Sex:

male/female

Dose descriptor:

LD50

Effect level:

340 mg/kg bw

Remarks on result:

other: 20% emulsion

Mortality:

All rats died within 3 to 150 minutes.(see Table below)

Clinical signs:

other: Twitching in eye muscles and those of eyelids and ears, then all over the body (extremities being the last); fluctuating body temperature (mostly subnormal), pulse and respiration rate increased and then became slow, irregular and weak; pupils first cont

Gross pathology:

No data

Phenol is a major component of the reaction mass and by its toxicity drives the hazard of the rection mass, so that phenol hazard data are applied in the hazard assessment.

Phenol: Oral toxicity in rats in relation to the concentration of aqueous phenol solution

Dose in mg/kg bw (number of rats)	Mortality (in %)	Time till death in minutes
2% Phenol in water (LD50 = 530 mg/kg bw)
400	1/5 (20)	25
500	4/10 (40)	15-150
600	7/10 (70)	19-50
700	8/10 (80)	14-60
800	10/10 (100)	10-90
5% Phenol in water (LD50 = 530 mg/kg bw)
400	1/15 (7)	20
500	6/15 (40)	10-30
600	11/15 (73)	3-80
700	9/10 (90)	4-50
10% Phenol in water (LD50 = 540 mg/kg bw)
500	4/10 (40)	15-35
600	6/10 (60)	10-50
700	9/10 (90)	10-120
800	9/10 (90)	7-60
20% Phenol in water (LD50 = 340 mg/kg bw)
300	6/15 (40)	5-45
400	9/15 (60)	15-60
500	15/15 (100)	5-55

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

After acute oral application in rats the LD50 varied between 340 and 540 mg/kg bw.

Executive summary:

The study is comparable to OECD Guideline 401 with acceptable restrictions (post exposure observation period 7 days, no necropsy and body weight data; unusual oral administration at application volumes <=1 ml).

Different amounts of aqueous solutions/emulsions containing 2, 5, 10 or 20% of phenol were orally administered to 5 -15 rats per dose group (equal numbers of males and females in each group). Phenol concentrations of 2, 5 or 10% resulted in the same degree of toxicity, the LD50 being 530, 530 or 540 mg/kg bw, respectively. The 20% emulsion was somewhat more toxic, the corresponding LD50 being 340 mg/kg bw. All of the animals that died within the study were found dead within 3 to 150 minutes. Clinical signs were twitching in muscles (starting with eye muscles), hypothermia, altered pulse and respiration rate (increased and later slow, irregular and weak), pupils first contracted and later on dilated, salivation, marked dyspnea, tremor and convulsions before death.

Conclusion: After acute oral application in rats the LD50 varied between 340 and 540 mg/kg bw.

Cross-reference 3

Reason / purpose for cross-reference:

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:

The study is comparable to OECD Guideline 401 with acceptable restrictions (partly limited documentation, e.g. no details on test substance or concentration used; only 4 males per dose; clinical signs not reported). Phenol is a constituent of the reaction mass so that phenol hazard data are applied in the hazard assessment.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: albino, no further data

Sex:

male

Details on test animals or test system and environmental conditions:

No details

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

no further details

Doses:

200, 400, 800, 1600 mg/kg bw

No. of animals per sex per dose:

4 males

Control animals:

other: untreated rats for evaluation of body eight gain

Details on study design:

Test procedure according to Federal Hazardous Substances Act (FHSA), published in the Fedetal Register (1961), Part 191, pages 7333-7341. Post exposure observation period 14 days; necropsy performed.

Statistics:

no data

Sex:

male

Dose descriptor:

LD50

Effect level:

650 mg/kg bw

95% CL:

490 - 860

Mortality:

See Table below. All deaths occurred on the first day after administration (no further details).

Clinical signs:

other: no data

Gross pathology:

Hyperemia and distention of the stomach and intestines upon autopsy of rats which died. No effects in survivors.

Other findings:

No data

Phenol is a major component of the reaction mass and by its toxicity drives the hazard of the rection mass, so that phenol hazard data are applied in the hazard assessment.

Acute oral toxicity of phenol

Dose in mg/kg bw	Mortality
200	0/4
400	0/4
800	3/4
1600	4/4

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In male rats the LD50 after oral application via gavage was 650 mg/kg bw (95% confidence limits: 490-860 mg/kg bw).

Executive summary:

The study is comparable to OECD Guideline 401 with acceptable restrictions (partly limited documentation, e.g. no details on test substance or concentration used; only 4 males per dose; clinical signs not reported).

Four male albino rats per dose received via gavage 200, 400, 800, or 1600 mg/kg bw in aqueous preparations. The post exposure observation period was 14 days. All deaths (only in the 2 high dose groups) occurred on the first day after administration. A slight but significant decrease in body weight was detected in survivors. Necropsy revealed hyperemia and distention of the stomach and intestines upon autopsy of rats which died; no effects were found in survivors.

Conclusion: In male rats the LD50 after oral application via gavage was 650 mg/kg bw (95% confidence limits: 490-860 mg/kg bw).

Cross-reference 4

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Conducted under OECD Guidelines

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 6-10 weeks.
- Housing: Animals were housed in groups of 5 by sex in grid floor stainless steel cages.
- Diet: Ad libitum, with the exception of an overnight fast prior to dosing. Food was re-introduced 3-4 hours after treatment. SQC Rat and Mouse Maintenance Diet No. 1, Expanded (Special Diets Services, Ltd., Stepfield, Witham, Essex, England). Food was considered to not contain any contaminant at a level that might have affected the objectives or integrity of the study.
- Water: Water was provided at all times and dispensed from glass water bottles. Water was considered to not contain any contaminant at a level that might have affected the objectives or integrity of the study.
- Acclimation period: At least 3 days.

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 degrees C
- Humidity: 40-70%
- Photoperiod: 12 hours light/12 hours dark

Route of administration:

oral: gavage

Vehicle:

other: 1% methylcellulose

Details on oral exposure:

Suspensions of BPA in 1% methylcellulose vehicle were administered once to each animal by oral gavage using a metal stomach tube attached to a disposable plastic syringe.

Doses:

5000 mg/kg and 2000 mg/kg

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

no

Details on study design:

A single oral dose of 5000 mg/kg BPA was administered by gavage to 5 male and 5 female Sprague Dawley rats after an overnight fast. At the request of the study sponsor, a second group of 10 animals (5 males, 5 females) was treated with a single oral dose of 2000 mg/kg. Animals were observed for overt signs of toxicity or behavioural changes at 1 and 4 hours after treatment and subsequently once daily for 14 days. Body weights were recorded on the day before treatment (day -1), the day of treatment (day 0), days 7 and 14, and at death. All animals were subjected to gross necropsy examination.

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

> 2 000 - <= 5 000 mg/kg bw

Mortality:

At 2000 mg/kg BPA, no animals died.
At 5000 mg/kg BPA, 1 male and 5 females died within 1-2 days after treatment.

Clinical signs:

other: At 5000 mg/kg BPA, major signs of toxicity noted on the day of dosing were lethargy, prostration, hunched posture, and piloerection. Three surviving animals were prostrate on the morning of day 1 and were found dead at afternoon death check approximately

Gross pathology:

Common findings at necropsy of animals that died during the study were associated with the liver and gastrointestinal tract. All animals necropsied at study termination were unremarkable.

BPA is one of the two main components (ca. 33%) of the reaction mass so that its hazard data are relevant for the hazard assessment of the reaction mass. This BPA study has been included as supporting study to demonstrate that acute oral toxicity of BPA is low so that phenol data are used for hazard characterisation of the reaction mass.

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The acute oral median lethal dose of BPA in the rat was confirmed to be in excess of 2000 mg/kg and was approximately 5000 mg/kg.

Executive summary:

A single oral dose of 5000 mg/kg BPA was administered by gavage to 5 male and 5 female Sprague Dawley rats after an overnight fast. At the request of the study sponsor, a second group of 10 animals (5 males, 5 females) was treated with a single oral dose of 2000 mg/kg. Animals were observed for overt signs of toxicity or behavioural changes at 1 and 4 hours after treatment and subsequently once daily for 14 days. Body weights were recorded on the day before treatment (day -1), the day of treatment, days 7 and 14, and at death. All animals were subjected to gross necropsy examination. At 5000 mg/kg BPA, 1 male and 5 females died within 1-2 days after treatment. Major signs of toxicity noted on the day of dosing were lethargy, prostration, hunched posture, and piloerection. Three surviving animals were prostrate on the morning of day 1 and were found dead at afternoon death check approximately 30 hours after dosing. At 2000 mg/kg BPA, no animals died, but all animals were lethargic or prostrate on the day of dosing. Occasional signs of chromodacryorrhoea and salivation were noted on the day of dosing and on day 1. All surviving animals from both dose groups showed gains in body weight at study termination. Common findings at necropsy of animals that died during the study were associated with the liver and gastrointestinal tract. All animals necropsied at study termination were unremarkable. The authors concluded that the acute oral median lethal dose of BPA in the rat was in excess of 2000 mg/kg and was approximately 5000 mg/kg.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of 4,4'-isopropylidenediphenol and phenol

EC Number:

904-653-0

IUPAC Name:

Reaction mass of 4,4'-isopropylidenediphenol and phenol

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 340 - <= 650 mg/kg bw

Based on:

test mat.

Remarks:

Phenol

Effect levels 2

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 2 000 - <= 5 000 mg/kg bw

Based on:

test mat.

Remarks:

BPA

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria