Registration Dossier

Read Across from terphenyl (CAS 26140 -60 -3) more specifically a Mixture or terphenyls and quarterphenyls; Key study: Acute oral toxicity (OECD 404) in rats: LD50 > 2000 mg/kg bw (LD50 = 2304 mg/kg bw)
Read Across from terphenyl (CAS 26140 -60 -3) more specifically a Mixture of terphenyls and quarterphenyls; Key study: Acute inhalation toxicity (OECD 403) in rats: LD50 > 3.8 mg/L air
Read Across from terphenyl (CAS 26140 -60 -3) more specifically a Mixture or terphenyls and quarterphenyls; Key study: Acute dermal toxicity (OECD 402) in rabbits: LD50 > 2000 mg/kg bw (LD50 > 5000 mg/kg bw)

Reference

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
In this justification, the read-across (bridging) concept is applied, based on the chemical structure of the potential analogues, their toxicokinetic behaviour and other available (eco-)toxicological data.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance Reaction mass of m-terphenyl and o-terphenyl and the source substance terphenyl (containing mainly m-terphenyl, o-terphenyl and only little p-terphenyl as well as a low percentage of quarterphenyls) used in this study belongs to the group of closely related aromatic hydrocarbons. Also known as diphenylbenzenes or triphenyls, they consist of a central benzene ring substituted with two phenyl groups. Obviously, the contained isomers are only different to a minor extent. Moreover, all isomers have common functional group(s). In addition, they were simulated to have the same breakdown products using the In vivo rat metabolism simulator and the Rat liver S9 metabolism simulator (OECD QSAR Toolbox v4.2).
Therefore both substances are expected to follow the same toxicokinetic pattern.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

source substance:
Mixture of terphenyls (ca. 60 %; mainly m- and o-terphenyls and only a minor content of p-terphenyl) and quarterphenyls (ca. 35 %)
structural formula: C18H14 and C24H18
The terphenyl substance consists of three constituents, each with their own Smiles notation and structural formula:
o-terphenyl: c(c(c(cccc1)c1)ccc2)(c(cccc3)c3)c2
m-terphenyl: c(c(cccc1)c1)(cccc2c(cccc3)c3)c2
p-terphenyl: c(c(cccc1)c1)(ccc(c(cccc2)c2)c3)c3
The quarterphenyls:
ortho-/ortho-:c1cccc(c1c1ccccc1)c1ccccc1c1ccccc1
ortho-/meta-: c1c(cccc1c1ccccc1c1ccccc1)c1ccccc1
ortho-/para-: c1cc(ccc1c1ccccc1)c1ccccc1c1ccccc1
meta-/meta-: c1c(cccc1c1cccc(c1)c1ccccc1)c1ccccc1
meta-/para-: c1cc(ccc1c1ccccc1)c1cccc(c1)c1ccccc1
para-/para-: c1cc(ccc1c1ccccc1)c1ccc(cc1)c1ccccc1
CAS 26140-60-3
EC No 247-477-3
purity: not specified

target substance:
Reaction mass of m-terphenyl and o-terphenyl (100 % m- and o-terphenyl)
structural formula: C18H14
The substance consists of two constituents, each with their own Smiles notation and structural formula:
o-terphenyl: c(c(c(cccc1)c1)ccc2)(c(cccc3)c3)c2
m-terphenyl: c(c(cccc1)c1)(cccc2c(cccc3)c3)c2
CAS -
EC No 904-797-4
purity: ≥ 90 - ≤ 100 % (w/w)

3. ANALOGUE APPROACH JUSTIFICATION
Reaction mass of m-terphenyl and o-terphenyl and Mixture of terphenyls (ca. 60 %) and quarterphenyls (ca. 35 %) belong to the group of closely related aromatic hydrocarbons. Terphenyls, also known as diphenylbenzenes or triphenyls, consist of a central benzene ring substituted with two phenyl groups.

Both chemicals are expected to be metabolised similarly building similar metabolites (“common breakdown product").
The similar findings (refer to data matrix outlined below) for both substances support the conclusion that similar molecules will be formed from both substances when applied systemically. In consequence, Mixture of terphenyls and quarterphenyls may perfectly serve as read-across substance for Reaction mass of m-terphenyl and o-terphenyl and vice versa. So, the available data on Mixture of terphenyls and quarterphenyls can be used to cover all systemic endpoints currently lacking from Reaction mass of m-terphenyl and o-terphenyl, making further testing obsolete.

4. DATA MATRIX
There is mainly physico-chemical data available on the toxicological properties of Reaction mass of m-terphenyl and o-terphenyl. Data on Mixture of terphenyls and quarterphenyls covers among others the toxicokinetic, acute toxicity, irritation / corrosion and genetic mutation in vitro. The identification and discussion of common properties will be based on available data including toxicological and physicochemical data.
The physical state of the two substances is solid (Reaction Mass of m-terphenyl and o-terphenyl is a cream colored solid block at room temperature; Mixture of terphenyls and quarterphenyl is a soft solid at room temperature, melting to a yellow liquid). Their melting point lies at 32 °C and 145 °C; their boiling point at 355°C and 343°C. Furthermore, their density is quite similar (1.11 x 10E3 kg/m3 at 20.0 ± 0.5 ºC and 1.133 x 10E3 kg/m3 at 25 ºC) and the vapour pressure is also in the same range (1.8 x 10E-2 Pa at 25 °C (corresponding to 1.7765 x 10E-7 atmosphere) and 1.6x10E-5 to 3.0x10E-14 atmosphere; the estimated vapor pressure of the o-, m- and p-terphenyls ranged from 4.3 x 10E-7 to 8.0 x 10E-10 atmosphere).
The available data for the following physico-chemical properties, which are relevant for absorption into living organisms, are very similar. Both substances are medium sized molecules with a molecular weight of 230.31 (Reaction mass of m-terphenyl and o-terphenyl) resp. 230 and 306 (terphenyls and quarterphenyls)), they are both insoluble and slightly soluble in water (Less than 1.0 x 10E-4 g/L of solution at 20.0 ± 0.5 °C (Reaction mass of m-terphenyl and o-terphenyl) and 0.151 mg/L at 25°C (Mixture of terphenyls and quarterphenyls), respectively). Moreover, they have a rather high logPow (3.01 to 5.94 (Reaction mass of m-terphenyl and o-terphenyl) and 5.86 at 22°C (Mixture of terphenyls and quarterphenyl)). Both chemicals are not readily biodegradable and they are not expected to be hydrolysed due to lack of functional groups. For Reaction mass of m-terphenyl and o-terphenyl a QSAR calculation has been performed for the Bioconcentration Factor (BCF). For both - m-terphenyl and o-terphenyl - a BCF of 2041 L/kg wet-wt (3.31 log BCF) was predicted. Mixture of terphenyls and quarterphenyl has a low potential for bioaccumulation in aquatic organisms.

There is only data available for the target substance Reaction mass of m-terphenyl and o-terphenyl for the following toxicological endpoints: Repeated dose toxicity oral and Toxicity to reproduction (fertility / developmental toxicity).
Moreover, there is data available for the source substance Mixture of terphenyls and quarterphenyls for the following endpoints: Acute toxicity oral, Acute toxicity dermal, Skin irritation / corrosion, Eye irritation /corrosion, Genetic toxicity in vitro.
The Read Across substance Mixture or terphenyls and quarterphenyls has been shown to be not acutely toxic and not irritating to the skin or the eyes. In addition, the Read Across substance has been shown to be not mutagenic. For Reaction mass of m-terphenyl and o-terphenyl a NOAEL of 100 mg/kg bw was derived for the endpoint Repeated dose toxicity oral and for reproduction / developmental toxicity, based on effects around parturition at 300 mg/kg/day.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 604 mg/kg bw

95% CL:

>= 2 247 - <= 2 940

Remarks on result:

other: Slope: 9.3

Remarks:

95 % Confidence Limits: 4.7 and 13.8

Sex:

male

Dose descriptor:

LD50

Effect level:

2 925 mg/kg bw

95% CL:

>= 2 414 - <= 3 518

Remarks on result:

other: Slope 11.2

Remarks:

95 % Confidence Limits: 3.9 and 18.5

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

2 304 mg/kg bw

95% CL:

>= 1 421 - <= 2 790

Remarks on result:

other: Slope. 9.4

Remarks:

95 % Confidence Limits: 1.8 and 17.0

Clinical signs:

Toxicity to the nervous system was suggested by several of the clinical abnormalities that were observed during the early part of this study. Sedation, ptosis, and ataxia were each observed in at least 12 animals by the first day after dosing and each occurred in a dosage-related manner. Prostration and lacrimation also occurred, but these abnormalities were observed in fewer animals. Gastrointestinal involvement was indicated by diarrhea, but this may have been induced by the corn oil used as the dosing vehicle.

Gross pathology:

Necropsy findings of gastrointestinal (GI) distension, discoloration of the intestines, and apparent gastrointestinal hemorrhage indicated that the GI tract was affected by this test material.

Acute Oral Toxicity to Rats Mean Body Weight and Mortality Summary

Dosage (mg/kg)	Mean body weight (Grams)			N° deaths / N° dosed	Days of death postdosing
Dosage (mg/kg)	Day 0	Day 7	Day 14	N° deaths / N° dosed	Days of death postdosing
Male rats
1984	247	301	352	0/5	-
2500	248	282	334	2/5	2,2
3150	251	278	326	2/5	1,2
3969	248	-	-	5/5	1,1,2,2,3
5000	238	-	-	5/5	1,2,2,2,2
Female rats
1984	181	210	235	1/5	1
2500	186	221	247	4/5	1,2,2,2
3150	179	209	228	4/5	1,2,2,2
3969	179	-	-	5/5	1,1,2,2,2
5000	174	-	-	5/5	1,1,1,2,2

Table 2
Acute Oral Toxicity to Rats Summary of Observations During Life
Observation Dosage (mg/kg)	No. Observed/No. Dosed*
Observation Dosage (mg/kg)	Male	Female	Combined	Comments
Sedation
1984	1/5	0/5	1/10	Day 0 only
2500	3/5	3/5	6/10	Days 1, 2, and 5
3150	2/5	3/5	5/10	Days 1, 2, and 5
3969	5/5	5/5	10/10	Days 0 thourgh 2
5000	4/5	5/5	9/10	Day 1 only
Ataxia
2500	2/5	0/5	2/10	Days 1 and 2
3150	1/5	1/5	2/10	Days 1 and 2
3969	1/5	4/5	O/J.0	Days 1 and 2
5000	1/5	3/5	4/10	Day 1 only
Prostration
3150	0/5	2/5	2/10	Day 1 only
3969	2/5	1/5	3/10	Day 1 only
5000	0/5	1/5	1/10	Day 1 only
Ptosis
2500	2/5	0/5	2/10	Days 1 and 2
3150	2/5	3/5	5/10	Days 1 and 2
3969	4/5	5/5	9/10	Days 0 through 2
5000	4/5	4/5	8/10	Day 1 only
Lacrimation
2500	0/5	1/5	1/10	Day 1 only
3150	0/5	3/5	3/10	Day 1 only
3969	2/5	0/5	2/10	Day 1 only
Diarrhea
1984	0/5	1/5	1/10	Day 1 only
2500	4/5	1/5	5/10	Days 1 and 2
3150	4/5	3/5	7/10	Days 1 and 2
3969	5/5	5/5	10/10	Day 1 only
5000	5/5	3/5	8/10	Day 1 only
Lack of Feces
3150	2/5	1/5	3/10	Days 1 and 2
3969	1/5	0/5	1/10	Day 2 only
Chromodacryorrhea
2500	2/5	0/5	2/10	Days 1 and 2
3969	1/5	0/5	1/10	Day 2 only
5000	2/5	0/5	2/10	Day 1 only
Porphyrin Around the Nose
2500	1/5	1/5	2/10	Days 1 and 2
3150	2/5	0/5	2/10	Day 2 only
3969	2/5	2/5	4/10	Days 1 and 2
5000	1/5	1/5	2/10	Day 1 only
Piloerection
3969	0/5	1/5	1/10	Day 1 only
Dark (Purple) Coloration of the Tail
2500	1/5	0/5	1/10	Day 1 only
Incomplete Administration ("Bakflush) of Test Material
3969	Ö/5	i/s	1/10	Day 0 only
*For the number of -living animals during the observation periods listed above, refer to Table 1.

Table 3
Acute Oral Toxicity to Rats Summary of Necropsy Observations
Observation Dosaqe (mg/kg)	No. Observed/No. Dosed
Observation Dosaqe (mg/kg)	Male	Female	Combined
Gastrointestinal Distension
1984	0/5	1/5	1/10
2500	1/5	2/5	3/10
3150	1/5	1/5	2/10
3969	3/5	1/5	4/10
5000	3/5	3/5	6/10
Dark and/or Red Discoloration of the Intestinal Tract
1984	0/5	1/5	1/10
2500	1/5	1/5	2/10
3150	1/5	2/5	3/10
3969	4/5	3/5	7/10
5000	3/5	4/5	7/10
Apparent Gastrointestinal Hemorrhage
5000	0/5	2/5	2/10
Urine Stained Fur
1984	0/5	1/5	1/10
2500	2/5	2/5	4/10
3150	2/5	2/5	4/10
3969	3/5	3/5	6/10
5000	4/5	5/5	9/10
Diarrheal Feces or Feces Stained Fur
1984	0/5	1/5	1/10
2500	2/5	1/5	3/10
3150	2/5	1/5	3/10
3969	4/5	3/5	7/10
5000	5/5	1/5	6/10
Lacrimation
1984	0/5	1/5	1/10
Excessive Salivation
3969	0/5	1/5	1/10
5000	0/5	1/5	1/10
Red Discharge from the Nose and/or the Eyes
1984	0/5	1/5	1/10
2500	1/5	2/5	3/10
3150	1/5	1/5	2/10
3969	2/5	3/5	5/10
5000	3/5	3/5	6/10
Red Material on the Forelegs (Apparently Rubbed off the Face)

2500	0/5	1/5	1/10
Pale Coloration of the Liver
1984	0/5	1/5	1/10
Autolysis of Internal Tissues
2500	1/5	2/5	3/10
3150	1/5	3/5	4/10
3969	1/5	3/5	4/10
5000	2/5	1/5	3/10

Interpretation of results:

not classified

Conclusions:

The acute oral LD50 for Mixture of terphenyls and quarterphenyls (CAS 26140-60-3) was calculated to be 2604 mg/kg bw with 95% CL of 2247 -2940 mg/kg.
For male rats, the acute oral LD50 was calculated to be 2925 mg/kg.
For female rates, it was calculated to be 2304 mg/kg bw.
The target substance Reaction mass of m-terphenyl and o-terphenyl and the source substance terphenyl (containing mainly m-terphenyl, o-terphenyl and p-terphenyl as well as ca. 35 % quarterphenyls) used in this study belong to the group of closely related aromatic hydrocarbons. Also known as diphenylbenzenes or triphenyls, they consist of a central benzene ring substituted with two phenyl groups.
Therefore, both substances are expected to follow the same toxicokinetic pattern. For the detailed procedure of the read-across principle and justifications, please refer to the analogue approach justification depicted above.

Executive summary:

When the test item (Toluene soluble terphenyl and quarterphenyls) was administered to fasted albino rats of both sexes, the acute oral LD50 was calculated to be 2604 mg/kg bw with 95% CL of 2247 -2940 mg/kg. For male rats, the acute oral LD50 was calculated to be 2925 mg/kg, and for female rates, it was calculated to be 2304 mg/kg bw. Observiations considered to be treatment related included sedation, ptosis, ataxia, prostration, lacrimation, and diarrhoea. Necropsy findings indicated that the gastrointestinal tract was affected.

The target substance Reaction mass of m-terphenyl and o-terphenyl and the source substance terphenyl (containing mainly m-terphenyl, o-terphenyl and p-terphenyl as well as ca. 35 % quarterphenyls) used in this study belong to the group of closely related aromatic hydrocarbons. Also known as diphenylbenzenes or triphenyls, they consist of a central benzene ring substituted with two phenyl groups.

Therefore both substances are expected to follow the same toxicokinetic pattern. For the detailed procedure of the read-across principle and justifications, please refer to the analogue approach justification depicted above.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 304 mg/kg bw

Reference

Endpoint:

acute toxicity: inhalation

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
In this justification, the read-across (bridging) concept is applied, based on the chemical structure of the potential analogues, their toxicokinetic behaviour and other available (eco-)toxicological data.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance Reaction mass of m-terphenyl and o-terphenyl and the source substance terphenyl (containing mainly m-terphenyl, o-terphenyl and only little p-terphenyl as well as a low percentage of quarterphenyls) used in this study belong to the group of closely related aromatic hydrocarbons. Also known as diphenylbenzenes or triphenyls, they consist of a central benzene ring substituted with two phenyl groups. Obviously, the contained isomers are only different to a minor extent. Moreover, all isomers have common functional group(s). In addition, they were simulated to have the same breakdown products using the In vivo rat metabolism simulator and the Rat liver S9 metabolism simulator (OECD QSAR Toolbox v4.2).
Therefore both substances are expected to follow the same toxicokinetic pattern.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

source substance:
Mixture of terphenyls (mainly m- and o-terphenyls and only a minor content of p-terphenyl) and quarterphenyls (ca. 25 %)
structural formula: C18H14 and C24H18
The terphenyl substance consists of three constituents, each with their own Smiles notation and structural formula:
o-terphenyl: c(c(c(cccc1)c1)ccc2)(c(cccc3)c3)c2
m-terphenyl: c(c(cccc1)c1)(cccc2c(cccc3)c3)c2
p-terphenyl: c(c(cccc1)c1)(ccc(c(cccc2)c2)c3)c3
The quarterphenyls:
ortho-/ortho-:c1cccc(c1c1ccccc1)c1ccccc1c1ccccc1
ortho-/meta-: c1c(cccc1c1ccccc1c1ccccc1)c1ccccc1
ortho-/para-: c1cc(ccc1c1ccccc1)c1ccccc1c1ccccc1
meta-/meta-: c1c(cccc1c1cccc(c1)c1ccccc1)c1ccccc1
meta-/para-: c1cc(ccc1c1ccccc1)c1cccc(c1)c1ccccc1
para-/para-: c1cc(ccc1c1ccccc1)c1ccc(cc1)c1ccccc1
CAS 26140-60-3
EC No 247-477-3
purity: not specified

target substance:
Reaction mass of m-terphenyl and o-terphenyl (100 % m- and o-terphenyl)
structural formula: C18H14
The substance consists of two constituents, each with their own Smiles notation and structural formula:
o-terphenyl: c(c(c(cccc1)c1)ccc2)(c(cccc3)c3)c2
m-terphenyl: c(c(cccc1)c1)(cccc2c(cccc3)c3)c2
CAS -
EC No 904-797-4
purity: ≥ 90 - ≤ 100 % (w/w)

3. ANALOGUE APPROACH JUSTIFICATION
Reaction mass of m-terphenyl and o-terphenyl and Mixture of terphenyls and quarterphenyls (ca. 2 5 %) belong to the group of closely related aromatic hydrocarbons. Terphenyls, also known as diphenylbenzenes or triphenyls, consist of a central benzene ring substituted with two phenyl groups.

Both chemicals are expected to be metabolised similarly building similar metabolites (“common breakdown product").
The similar findings (refer to data matrix outlined below) for both substances support the conclusion that similar molecules will be formed from both substances when applied systemically. In consequence, Mixture of terphenyls and quarterphenyls may perfectly serve as read-across substance for Reaction mass of m-terphenyl and o-terphenyl and vice versa. So, the available data on Mixture of terphenyls and quarterphenyls can be used to cover all systemic endpoints currently lacking from Reaction mass of m-terphenyl and o-terphenyl, making further testing obsolete.

4. DATA MATRIX
There is mainly physico-chemical data available on the toxicological properties of Reaction mass of m-terphenyl and o-terphenyl. Data on Mixture of terphenyls and quarterphenyls covers the acute toxicity to inhalation endpoint and genetic mutation in vitro and in vivo endpoint. The identification and discussion of common properties will be based on available data including toxicological and physicochemical data.
The physical state of the two substances is solid (Reaction Mass of m-terphenyl and o-terphenyl is a cream coloured solid block at room temperature; Mixture of terphenyls and quarterphenyls is a soft solid melting to yellow liquid at room temperature). Their melting point lies at 32 °C and 40-70 °C; their boiling point at 355°C and approximately 400 °C. Furthermore, their density is quite similar (1.11 x 10E3 kg/m3 at 20.0 ± 0.5 ºC and 1.041 x 10E3 kg/m3 at 25 ºC or 1.081 kg/m³ at 60°C) and the vapour pressure is expected to be in the same range (1.8 x 10E-2 Pa at 25 °C, corresponding to 1.7765 x 10E-7 atmosphere for Reaction mass of m-terphenyl and o-terphenyl and 11 mm Hg at 200°c for Mixture of terphenyls and quarterphenyls); the estimated vapour pressure of the o-, m- and p-terphenyls ranged from 4.3 x 10E-7 to 8.0 x 10E-10 atmosphere).
The available data for the following physico-chemical properties, which are relevant for absorption into living organisms, are very similar. Both substances are medium sized molecules with a molecular weight of 230.31 (Reaction mass of m-terphenyl and o-terphenyl) resp. 230 and 306 (terphenyls and quarterphenyls), they are both either insoluble expected to be insoluble to slightly soluble in water (Less than 1.0 x 10E-4 g/L of solution at 20.0 ± 0.5 °C (Reaction mass of m-terphenyl and o-terphenyl)). Moreover, they have a rather high logPow (3.01 to 5.94 (Reaction mass of m-terphenyl and o-terphenyl) and 5.86 at 22°C (Mixture of terphenyls and quarterphenyls)). Both chemicals are not readily biodegradable and they are not expected to be hydrolysed due to lack of functional groups. For Reaction mass of m-terphenyl and o-terphenyl a QSAR calculation has been performed for the bioconcentration factor (BCF). For both - m-terphenyl and o-terphenyl - a BCF of 2041 L/kg wet-wt (3.31 log BCF) was predicted. Mixture of terphenyls and quarterphenyl has a low potential for bioaccumulation in aquatic organisms.

There is only data available for the target substance Reaction mass of m-terphenyl and o-terphenyl for the following toxicological endpoints: Repeated dose toxicity oral and Toxicity to reproduction (fertility / developmental toxicity).
Moreover, there is data available for the Read Across substance Mixture of terphenyls and quarterphenyls for the following endpoints: Acute toxicity to inhalation, Genetic toxicity in vitro and Genetic toxicity in vivo.
The Read Across substance Mixture or terphenyls and quarterphenyls has been shown to be not mutagenic. For Reaction mass of m-terphenyl and o-terphenyl a NOAEL of 100 mg/kg bw was derived for the endpoint Repeated dose toxicity oral and for reproduction / developmental toxicity, based on effects around parturition at 300 mg/kg/day.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 3.8 mg/L air

Exp. duration:

4 h

Mortality:

No deaths occurred (See Table 1).

Clinical signs:

other: During exposure observations in the 3.8 mg/L, 3.7 mg/L and heated control groups salivation and red material around eyes were observed (in 3.7 mg/L group only). Discharge from nose was observed in the 3.6 mg/L group. Immediate post-exposure observations i

Body weight:

All groups gained body weight throughout the post-exposure period.

Gross pathology:

There were no gross pathology abnormalities observed in any of the animals during necropsy examinations.

Three groups of six male and six female rats per group were exposed once to atmospheres of aerosolized test item. Two additional exposures (controls) were performed using house-conditioned air only. All chamber atmospheres were heated during exposure except for one control exposure and one test item exposure. No deaths occurred. The mean exposure levels ranged from 3.6 mg/L to 3.8 mg/L. Therefore, the LC50 is assumed to be greater than 3.8 mg of the test item per liter of air. The nominal/analytical concentration ratios indicate some preferential impaction of the test material on the animals, cages, and chamber walls (Table 1). Particle-size analyses, including mass median aerodynamic diameter (MMAD), geometric standard deviation, and percent of particles less than 10 microns, are given for each test exposure level in Table 2. The percentage of particles, in the chamber, less than 10 microns ranged between 99.0 and 99.1. The MMAD for the exposures was between 2.27 and 2.38 microns, with the geometric standard deviation between 1.83 and 1.90.

During exposure observations in the 3.8 mg/L, 3.7 mg/L and heated control groups were salivation and red material around eyes (in 3.7 mg/L group only). Discharge from nose was observed in the 3.6 mg/L group.

Immediate post-exposure observations included red encrustation about eyes and nose, laboured breathing, salivation, wet fur on-the ventral side (due to salivation), and fur coated with test material (Table 3). Salivation, wet fur on the ventral side (due to salivation), and red encrustation about the nose were also noted on the heated chamber control animals. Post-exposure Day 2 signs of toxicity included red encrustation about eyes and nose and fur coated with test material (Table 4). On post-exposure Days 7 and 14, these observations were no longer evident. No observations were seen in the control groups during post-exposure Days 2, 7, and 14.

All groups gained body weight throughout the post-exposure period (Tables 5). There were no gross pathology abnormalities observed in any of the animals during necropsy examinations.

In conclusion, toluol soluble terphenyl and quarterphenyls at mean exposure concentrations of 3.6 to 3.8 mg/L in air caused some very short-term irritation to the respiratory tract and sensory organs. In the absence of any deaths, the LC50 is assumed to be greater than 3.8 mg/L.

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 for Mixture of toluol soluble terphenyls and quarterphenyls was determined to be above the maximum attainable concentration of 3.8 mg/L air (males/females)
The target substance Reaction mass of m-terphenyl and o-terphenyl and the source substance Mixed toluol soluble terphenyls and quarterphenyls used in this study belong to the group of closely related aromatic hydrocarbons. Also known as diphenylbenzenes or triphenyls, they consist of a central benzene ring substituted with two phenyl groups.
Therefore, both substances are expected to follow the same toxicokinetic pattern. For the detailed procedure of the read-across principle and justifications, please refer to the analogue approach justification depicted above.

Executive summary:

Three groups of 6 male and 6 female Sprague-Dawley rats per group were each exposed once for 4 hours to atmospheres of aerosolized a Mixture of toluol soluble terphenyls and quarterphenyls. Mean exposure concentrations ranged from 3.6, 3.7 and 3.8 mg of the test item (vapour/aerosol) per liter of air. 3.8 mg/L was the higher attainable mean concentration. The chamber atmospheres were operated at elevated ambient temperatures. Three single-concentratinos exposures (two concentrations with heated chamber air and test material and one with ambient chamber air and heated test material) and two control exposures (ambient house-conditioned or heated chamber air) were performed. Exposure was followed by a 14 -day observation period and subsequent necropsy. No death occurred at the higher attainable level or lower levels. During the exposure observations included salivation, red material around eyes, and discharge from nose. Immediately after exposure, notable observations included red encrustation around the nose and eyes, laboured breathing, salivation, wet fur on the ventral side (due to salivation), and fur coated with test material. Post-exposure observations included red encrustation around eyes and nose and fur coated with test material. By post-exposure Day 7, all animals appeared in good health. All animal groups gained weight throughout the 14 -day post-exposure period. terminal necropsy findings indicated that there were no gross abnormalities in any of the test animals. Based on the test results, the test item at mean exposure concentrations of 3 .6 to 3.8 mg/L in air caused some short term irritation to the respiratory tract and sensory organs. The LC50 for the test item is assumed to be greater than 3.8 mg/L, which was the maximum attainable concentration.

The target substance Reaction mass of m-terphenyl and o-terphenyl and the source substance Mixed toluol soluble terphenyls and quarterphenyls used in this study belong to the group of closely related aromatic hydrocarbons. Also known as diphenylbenzenes or triphenyls, they consist of a central benzene ring substituted with two phenyl groups.

Therefore, both substances are expected to follow the same toxicokinetic pattern. For the detailed procedure of the read-across principle and justifications, please refer to the analogue approach justification depicted above.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

3 800 mg/m³

Reference

Endpoint:

acute toxicity: dermal

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
In this justification, the read-across (bridging) concept is applied, based on the chemical structure of the potential analogues, their toxicokinetic behaviour and other available (eco-)toxicological data.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance Reaction mass of m-terphenyl and o-terphenyl and the source substance terphenyl (containing mainly m-terphenyl, o-terphenyl and only little p-terphenyl as well as a low percentage of quarterphenyls) used in this study belong to the group of closely related aromatic hydrocarbons. Also known as diphenylbenzenes or triphenyls, they consist of a central benzene ring substituted with two phenyl groups. Obviously, the contained isomers are only different to a minor extent. Moreover, all isomers have common functional group(s). In addition, they were simulated to have the same breakdown products using the In vivo rat metabolism simulator and the Rat liver S9 metabolism simulator (OECD QSAR Toolbox v4.2).
Therefore both substances are expected to follow the same toxicokinetic pattern.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

source substance:
Mixture of terphenyls (ca. 60 %; mainly m- and o-terphenyls and only a minor content of p-terphenyl) and quarterphenyls (ca. 35 %)
structural formula: C18H14 and C24H18
The terphenyl substance consists of three constituents, each with their own Smiles notation and structural formula:
o-terphenyl: c(c(c(cccc1)c1)ccc2)(c(cccc3)c3)c2
m-terphenyl: c(c(cccc1)c1)(cccc2c(cccc3)c3)c2
p-terphenyl: c(c(cccc1)c1)(ccc(c(cccc2)c2)c3)c3
The quarterphenyls:
ortho-/ortho-:c1cccc(c1c1ccccc1)c1ccccc1c1ccccc1
ortho-/meta-: c1c(cccc1c1ccccc1c1ccccc1)c1ccccc1
ortho-/para-: c1cc(ccc1c1ccccc1)c1ccccc1c1ccccc1
meta-/meta-: c1c(cccc1c1cccc(c1)c1ccccc1)c1ccccc1
meta-/para-: c1cc(ccc1c1ccccc1)c1cccc(c1)c1ccccc1
para-/para-: c1cc(ccc1c1ccccc1)c1ccc(cc1)c1ccccc1
CAS 26140-60-3
EC No 247-477-3
purity: not specified

target substance:
Reaction mass of m-terphenyl and o-terphenyl (100 % m- and o-terphenyl)
structural formula: C18H14
The substance consists of two constituents, each with their own Smiles notation and structural formula:
o-terphenyl: c(c(c(cccc1)c1)ccc2)(c(cccc3)c3)c2
m-terphenyl: c(c(cccc1)c1)(cccc2c(cccc3)c3)c2
CAS -
EC No 904-797-4
purity: ≥ 90 - ≤ 100 % (w/w)

3. ANALOGUE APPROACH JUSTIFICATION
Reaction mass of m-terphenyl and o-terphenyl and Mixture of terphenyls (ca. 60 %) and quarterphenyls (ca. 35 %) belong to the group of closely related aromatic hydrocarbons. Terphenyls, also known as diphenylbenzenes or triphenyls, consist of a central benzene ring substituted with two phenyl groups.

Both chemicals are expected to be metabolised similarly building similar metabolites (“common breakdown product").
The similar findings (refer to data matrix outlined below) for both substances support the conclusion that similar molecules will be formed from both substances when applied systemically. In consequence, Mixture of terphenyls and quarterphenyls may perfectly serve as read-across substance for Reaction mass of m-terphenyl and o-terphenyl and vice versa. So, the available data on Mixture of terphenyls and quarterphenyls can be used to cover all systemic endpoints currently lacking from Reaction mass of m-terphenyl and o-terphenyl, making further testing obsolete.

4. DATA MATRIX
There is mainly physico-chemical data available on the toxicological properties of Reaction mass of m-terphenyl and o-terphenyl. Data on Mixture of terphenyls and quarterphenyls covers among others the toxicokinetic, acute toxicity, irritation / corrosion and genetic mutation in vitro. The identification and discussion of common properties will be based on available data including toxicological and physicochemical data.
The physical state of the two substances is solid (Reaction Mass of m-terphenyl and o-terphenyl is a cream coloured solid block at room temperature; Mixture of terphenyls and quarterphenyls is a soft solid a room temperature, melting to a yellow liquid). Their melting point lies at 32 °C and 145 °C; their boiling point at 355°C and 343°C. Furthermore, their density is quite similar (1.11 x 10E3 kg/m3 at 20.0 ± 0.5 ºC and 1.133 x 10E3 kg/m3 at 25 ºC) and the vapour pressure is also in the same range (1.8 x 10E-2 Pa at 25 °C (corresponding to 1.7765 x 10E-7 atmosphere) and 1.6x10-5to 3.0x10E-14 atmosphere; the estimated vapour pressure of the o-, m- and p-terphenyls ranged from 4.3 x 10E-7 to 8.0 x 10E-10 atmosphere).
The available data for the following physico-chemical properties, which are relevant for absorption into living organisms, are very similar. Both substances are medium sized molecules with a molecular weight of 230.31 (Reaction mass of m-terphenyl and o-terphenyl) resp. 230 and 306 (terphenyls and quarterphenyls)), they are both insoluble and slightly soluble in water (Less than 1.0 x 10E-4 g/L of solution at 20.0 ± 0.5 °C (Reaction mass of m-terphenyl and o-terphenyl) and 0.151 mg/L at 25°C (Mixture of terphenyls and quarterphenyls), respectively). Moreover, they have a rather high logPow (3.01 to 5.94 (Reaction mass of m-terphenyl and o-terphenyl) and 5.86 at 22°C (Mixture of terphenyls and quarterphenyls)). Both chemicals are not readily biodegradable and they are not expected to be hydrolysed due to lack of functional groups. For Reaction mass of m-terphenyl and o-terphenyl a QSAR calculation has been performed for the Bioconcentration factor (BCF). For both - m-terphenyl and o-terphenyl - a BCF of 2041 L/kg wet-wt (3.31 log BCF) was predicted. Mixture of terphenyls and quarterphenyls has a low potential for bioaccumulation in aquatic organisms.

There is only data available for the target substance Reaction mass of m-terphenyl and o-terphenyl for the following toxicological endpoints: Repeated dose toxicity oral and Toxicity to reproduction (fertility / developmental toxicity).
Moreover, there is data available for the Read Across substance Mixture of terphenyls and quarterphenyls for the following endpoints: Acute toxicity oral, Acute toxicity dermal, Skin irritation / corrosion, Eye irritation /corrosion, Genetic toxicity in vitro.
The Read Across substance Mixture or terphenyls and quarterphenyls has been shown to be not acutely toxic and not irritating to the skin or the eyes. In addition, the Read Across substance has been shown to be not mutagenic. For Reaction mass of m-terphenyl and o-terphenyl a NOAEL of 100 mg/kg bw was derived for the endpoint Repeated dose toxicity oral and for reproduction / developmental toxicity, based on effects around parturition at 300 mg/kg/day.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Sex:

male

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

No deaths were observed in animals of either sex.

Clinical signs:

All clinical abnormalities observed during this study were considered to result from direct contact between the test material and the skin in the exposed area. Erythema of the skin occurred in nine animals. The duration of this effect ranged from two to thirteen days in individual, affected animals. Edema of the skin was observed in one female and two male animals on the first day after test material administration. Areas of inhibited growth of fur occurred in one female and two male animals and were observed on the last three days of the study.

Gross pathology:

At necropsy, most of the findings reflected the effect of direct contact of the skin in the exposed area with the test material. Redness of the skin was observed in two male and three female animals. Areas of inhibited fur growth occurred in one male and two female rabbits. Hardened skin was observed in one male animal. Raised skin occurred in one female animal. One animal of each sex had defatted skin. Both kidneys of one male animal had pitted exteriors, but this was not considered to represent toxicity of the test material.

Acute Dermal Toxicity to Rabbits Mean Body Weight and Mortality Summary

Dosage (mg/kg)	Mean body weight (Kg)			N° deaths / N° dosed	Days of death postdosing
Dosage (mg/kg)	Day 0	Day 7	Day 14	N° deaths / N° dosed	Days of death postdosing
Male rats
5000	2.58	2.78	3.00	0/5	-
Female rats
5000	2.62	2.78	3.03	0/5	-

Interpretation of results:

not classified

Conclusions:

The acute dermal LD50 for Mixture of terphenyls and quarterphenyls was determined to be above 5000 mg/kg bw.
The target substance Reaction mass of m-terphenyl and o-terphenyl and the source substance terphenyl (containing mainly m-terphenyl, o-terphenyl and p-terphenyl as well as ca. 35 % quarterphenyls) used in this study belong to the group of closely related aromatic hydrocarbons. Also known as diphenylbenzenes or triphenyls, they consist of a central benzene ring substituted with two phenyl groups.
Therefore both substances are expected to follow the same toxicokinetic pattern. For the detailed procedure of the read-across principle and justifications, please refer to the analogue approach justification depicted above.

Executive summary:

No deaths followed a dermal application of 5000 mg/kg bw of Toluene soluble terphenyl and quarterphenyls to the shaved and abraded dorsal surface of albino of both sexes. Therefore, the acute dermal LD50 of this material is considered to be in excess of 5000 mg/kg bw. Clinical abnormalities included erythema, edema, and inhibited growth of fur in the exposed area.

The target substance Reaction mass of m-terphenyl and o-terphenyl and the source substance terphenyl (containing mainly m-terphenyl, o-terphenyl and p-terphenyl as well as ca. 35 % quarterphenyls) used in this study belong to the group of closely related aromatic hydrocarbons. Also known as diphenylbenzenes or triphenyls, they consist of a central benzene ring substituted with two phenyl groups.

Therefore, both substances are expected to follow the same toxicokinetic pattern. For the detailed procedure of the read-across principle and justifications, please refer to the analogue approach justification depicted above.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

There are no data available for the target substance. However, several reliable test results are available for structurally related read across substances. The results of these will be described in the following.

Acute oral toxicity:

The key acute oral toxicity test was conducted with the structurally related read across substance Mixture of terphenyls and quarterphenyls according to the OECD 401 guideline and in compliance with GLP. Both male and female Sprague Dawley rats were exposed to a suspension of Mixture of toluene soluble terphenyl and quarterphenyls in corn oil via oral gavage, in one of the following concentrations: 1984, 2500, 3150 or 5000 mg/kg bw. Following administration of the test substance the animals were observed for 14 days. The following LD50 values were reported: 2604, 2925 and 2304 mg/kg bw, combined for both sexes, for males and for females, respectively. Toxicity to the nervous system was suggested by several of the clinical abnormalities that were observed. Furthermore, necropsy findings indicated that Mixture of terphenyls and quarterphenyls affected the gastrointestinal tract.

Furthermore, a supporting read across test results is included. The acute oral toxicity tests were conducted with twenty-two different heat transfer fluids used in solar collectors. Included among these were three fluids that had been used in collector installations for period of one to three years. The results of present tests, combined with data on other teat transfer fluids supplied by their manufacturers, and published data, provide an overview of the acute toxicological properties for these fluids when ingested by rats. Their Gosselin's acute oral toxicity ratings range from 1 (practically nontoxic) to 3 (moderately toxic). Most fluids have the rating 1. The acute oral toxicity of fluids used in solar collectors is sufficiently low to suggest that accidental ingestion of doses to produce a lethal effect is not very probable in normal use.

Moreover, an acute oral toxicity test with the structurally related read across substance Mixed of terphenyls is included, in which 5 rats/sex were dosed with 5000 mg/kg bw of Mixed terphenyls, followed by an observation period of 14 days. A dose range finding in 1 animal/sex was conducted at 1000, 2000 and 2600 mg/kg. There was no mortality nor clinical observations up to 5000 mg/kg bw, and body weight and gross postmortem findings did not demonstrate relevant deviations from control animals in the laboratory. In conclusion, the oral LD₅₀of Mixed terphenyls in rats is greater than 5000 mg/kg bw.

Acute inhalation toxicity:

To assess acute inhalation toxicity of the structurally related read across substance Mixture of terphenyls and quarterphenyls a test was set up according to the OECD 403 guideline (GLP-compliant) (= key study), in which a mixture of terphenyls and quarterphenyls was administered to Sprague Dawley rats via aerosol during 4 hours, after which the animals were observed for a period of 14 days. Exposure concentrations were 3.6, 3.7 and 3.8 mg/L (two concentrations with heated chamber air and test material and one with ambient chamber air and heated test material). An LD50 (male/female) > 3.8 mg/L air was reported. This concentration was the maximum attainable concentration. Immediate post exposure observations included red encrustation around eyes and nose, laboured breathing and salivation. On post-exposure days 7 and 14 these observations were no longer evident. No gross pathology abnormalities were observed in any of the animals during necropsy examinations.

Furthermore, a study has been made of certain aspects of the toxicology of organic polyphenyl compounds proposed for use as moderator-coolants in atomic reactors. Acute inhalation toxicity testing was performed with moderator-coolants o-terphenyl (OTP), m-terphenyl (MTP), p-terphenyl (PTP), terphenyl mixture (OMRE) and irradiated terphenyl mixture (ROMRE). Monoisopropylbiphenyl and o- and m-terphenyl were the only polyphenyls that caused death after inhalation, although all of the compounds produced some of the following symptoms: nasal congestion with rhinitis, lachrymation, laboured respiration, erythema of the ears and paws. The following histopathologic changes were also observed: acute tracheal necrosis, acute tracheobronchitis, pulmonary oedema, bronchopneumonia, atelectasis, and petechial haemorrhages. All such toxic effects can be prevented by protective clothing and respirators.

As no details are available on the actual composition and purity of the employed substances this result can not be used for classification.

Acute dermal toxicity:

The key study for acute dermal toxicity was conducted with the structurally related read across substance Mixture of toluene soluble terphenyls and quarterphenyls according to a GLP and OECD 402 guidelines. New Zealand White rabbits were exposed to 5000 mg/kg bw Mixture of toluene soluble terphenyls and quarterphenyls during 24 hours. The post exposure observation period was 24 hours. For both females and males the LD50 reported was > 5000 mg/kg bw. At necropsy most of the findings reflected the effects of direct contact of the skin with the test material.

Moreover, an acute dermal application of Mixed terphenyls to 5 male and 5 female rabbits under occlusive dressing for 24 hours did not result in mortality, severe clinical findings and gross postmortem findings during a 14 -day observation period.

Based on the lack of acute toxicity found for the Read Across substance terphenyl (CAS 26140 -60 -3) via the different routes, for Reaction mass of m-terphenyl and o-terphenyl no classification for acute toxicity according to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulations No 1272/2008 is warranted.