A mixture of branched and linear C7-C9 alkyl 3-[3-(2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxyphenyl]propionates

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

This read-across is based on the hypothesis that source and target substances have similar toxicological properties because of their structural similarities i.e. different compounds which have the same type of effects. This prediction is supported by the toxicological data on the substances themselves and predicted toxicokinetics of the substances. The target substance (Chiguard 5599) is a UVCB substance with 4 constituents which are a mixture of branched and linear C7-C9 alkyl 3-[3-(2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxyphenyl]propionates and Benzenepropanoic acid, 3-(1,3-dihydro-2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxy-. The C8 alkyl component is the main constituent (typical concentration: 91.24%). The source substance (Tinuvin 1130) is a multi-constituent substance with 2 main constituents which are Poly(oxy-1,2-ethanediyl), alpha-(3-(3-(2H-benzotriazol-2-yl)-5-(1,1- dimethylethyl)-4-hydroxyphenyl)-1-oxopropyl)-omega-hydroxy- and Poly(oxy-1,2-ethanediyl), alpha-(3-(3-(2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxopropyl)-omega-(3-(3-(2H- benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxopropoxy)- (≥40 and ≥30% typical concentration, respectively). The target substance (Chiguard 5599) and source substance (Tinuvin 1130) have a structurally similar backbone which is benzotriazole with an attached phenol and isopropyl linked at the ortho-position and a longer C(n)-branched and linear alkyl esters chain. Therefore, the source and the target substances share structural similarities with common functional groups and side chains varying in their length. The structural differences consist of an alkyl chain which is C7-C9 in Chiguard 5599 and in Tinuvin 1130 diethyl ether branched chains (C6-C7). There is also an esterification reaction combining the two components (CAS No. 104810-48-2) to form CAS No. 104810-47-1. These differences are chemically simple structures and their impact on the read across is discussed further below. The data gap for the target substance Chiguard 5599 is a screening for developmental toxicity study (Annex VIII, 8.7.1). According to Annex VIII 8.7.1, a prenatal developmental study may be submitted to fill this data gap. No reliable data on pre-natal developmental toxicity of Chiguard 5599 is available. Therefore, read-across from an existing pre-natal developmental study of the source substance, Tinuvin 1130, is considered as an appropriate adaptation to the standard information requirements of Annex VIII 8.7.1 of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation

Data source

Reference

Reference Type:

other: Body responsible for the test

Title:

Unnamed

Year:

2014

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: 92/69/EEC

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene); α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)

EC Number:

400-830-7

EC Name:

A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene); α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)

IUPAC Name:

400-830-7

Test animals

Species:

other: Rat (Tif: RAif (SPF))

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: PEG 300

Details on exposure:

Method of administration or exposure: Gavage

No. of animals per sex per dose:

Number of dams and doses
24 at 0 mg/kg or mg/1
24 at 1 mg/kg or mg/1
24 at 30 mg/kg or mg/1
24 at 150 mg/kg or mg/1

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Details on maternal toxic effects:
No deaths treatment-related occurred. Maternal bodyweight gain was reduced at 150 mg/kg.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
Effects on fetus - Gross:
There were no dead or absorbed foetuses. Numbers of live foetuses/litter and foetal weights were comparable between the groups.

Effects on fetus - Soft tissue:
Enlarged thymus was observed in a small group of foetuses from all groups. Accessory lobulets on the liver were observed in 2, 2 and 1 foetuses of groups 2, 3and 4 respectively.

Effects on fetus - Skeletal:
No skeletal malformations were observed. A significant increase in the incidence of litters affected with asymmetrically shaped sternebrae in group 4. This was
attributed to delayed ossification, related to maternal toxicity.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Basis for effect level:

other: embryotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Read-Across Justification: Full report is attached in study summary

3 Analogue approach justification

3.1. Physicochemical properties

Physicochemical data shows that the physicochemical properties of the target and source substances are similar as outlined in the data matrix (Table 3). Both are liquids and the structural differences in the side chains do not significantly influence the physicochemical properties of both substances, i.e. vapour pressure and water solubility. The partition coefficient (Log Kow) for the target substance (Chiguard 5599) is log Pow 9.2 at 25°C while the calculated values for the source substance (Tinuvin 1130) are log Pow 4.74 (CAS No. 104810-48-2) and log Pow 10.73 (CAS No. 104810-47-1). The water solubility for both of the target and source substances is slightly soluble (<0.3mg/L at 20°C for the target substance and 7.7 mg/L at 20°C for the source substance). Neither of the substances is volatile, with a vapour pressure of 0.000003 Pa at 25°C for the target substance and 0.000048 Pa at 25°C for the source substance.

3.2. Toxicokinetics

No experimental data on absorption, distribution, metabolism or excretion is available for the source or target substance. The toxicokinetic assessment is based on physicochemical properties of the substances and available in vivo toxicological data.

Physicochemical data

The source and target chemical have similar toxicokinetic behaviour based on their similar physicochemical properties (Table 3): physical state (liquid), slight solubility in water (0.1 – 100 mg/L) and high calculated log Pow values. This indicates that oral absorption may be low and occur via the lymphatic system; the in vivo studies confirm absorption via the oral route does occur. The physical forms (liquid) and low vapour pressures of both substances (Chiguard 5599: 0.000003 Pa at 25°C; Tinuvin 1130: 0.000048 Pa at 25°C) indicate low volatility, so respiratory exposure is expected to be low. The low water solubility of both substances indicate low dermal uptake while the high log Pow values are indicators for high uptake into the stratum corneum but little or no penetration into the lower layers of the epidermis and dermis. Overall, the physical states, high calculated log Pow values and poor water solubility indicate that dermal absorption is unlikely.

Both of the target and source substances are not expected to undergo hydrolysis due to a lack of hydrolytic functional groups and so are likely to be present in the body in non-ionised forms, which facilitates distribution. As both substances are lipophilic, they are likely to accumulate in fat during chronic exposure with high doses. There is no direct evidence to indicate the major route of excretion of the substances however the fraction of the substance that is absorbed is expected to be excreted in the urine and water solubility will be increased during metabolic transformation.

Other data in the literature

There are no available experimental data for toxicokinetics for either the target or source substance.

Available in vivo toxicological data

The available in vivo data from both substances indicate no evidence of systemic toxicity upon acute oral exposure in rats but in the 28 day repeated toxicity study in rats there was evidence of the liver being the target organ for toxicity for both Chiguard 5599 (NOAEL = 2 mg/kg bw/day) and Tinuvin 1130 (NOAEL = 10 mg/kg bw/day; see Section 3.3.1), which may compromise detoxification. The pre-natal developmental toxicity study in rats from Tinuvin 1130 indicates maternal toxicity but no teratogenic effects and limited foetal exposure is expected for both substances. The in vivo dermal studies (irritation, sensitisation) confirm that dermal absorption of Chiguard 5599 is poor but Tinuvin 1130 is a skin sensitizer so some dermal absorption must occur.

3.3 Comparison of data from human health endpoints

3.3.1 Toxicity data of the target and source substances

As is presented in the data matrix (Table 3), the acute oral and dermal toxicity data show similar low toxicity for the source and the target chemicals. No skin or eye irritation was noted for either chemical. Both chemicals have negative in vitro bacterial mutagenicity Ames test results and negative in vivo micronucleus genotoxicity assays in rats. Neither substance is genotoxic. In the 28 day repeated dose toxicity studies, both substances were noted to cause biochemical, haematogical and organ weight changes with the liver being a target organ. A NOAEL of 2 mg/kg bw/day was identified in the Chiguard 5599 28 day repeated dose toxicity while no specific NOAEL was indicated for Tinuvin 1130. However, it was noted in the inquiry result comments that the dose causing no toxic effect was between 10 (lowest dose tested) and 50 mg/kg bw/day, so this would indicate a NOAEL of 10 mg/kg bw/day. So, there is similar potency and the same target organ (liver) for both the target and source substance. The full study report was not available for either chemical and the harmonised classification in the ECHA C&L inventory (checked 15-07-15) for Tinuvin 1130 does not indicate that a STOT-RE classification was warranted and we have concluded it is not required for Chiguard 5599 either. The only difference in human health effects is in skin sensitisation. The source substance, Tinuvin 1130 is a skin sensitizer in the guinea pig maximization test while the target substance, Chiguard 5599 is not a skin sensitizer in the same test.

The data gap for the target substance Chiguard 5599 is a screening for developmental toxicity study (Annex VIII, 8.7.1). According to Annex VIII 8.7.1, a prenatal developmental study may be submitted to fill this data gap. No reliable data on pre-natal developmental toxicity of Chiguard 5599 is available. Therefore, read-across from an existing pre-natal developmental study of the source substance, Tinuvin 1130 is considered as an appropriate adaptation to the standard information requirements of Annex VIII 8.7.1 of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation. The read-across pre-natal developmental toxicity study (RL2) was conducted according to 92/69 EEC and in compliance with GLP. In the study, Tinuvin 1130 was administered to rats (Tif: RAif (SPF)); 24/sex/dose) orally in PEG 300 at dose levels of 0, 1, 30, 500 mg/kg bw/day during DG 6-15. No deaths treatment-related occurred. Maternal bodyweight gain was reduced at 150 mg/kg bw/day. There were no dead or absorbed foetuses. Numbers of live foetuses/litter and foetal weights were comparable between the groups. Enlarged thymus was observed in a small group of foetuses from all groups. Accessory lobulets on the liver were observed in 2, 2 and 1 foetuses of groups 2, 3 and 4 respectively. No skeletal malformations were observed. A significant increase in the incidence of litters affected with asymmetrically shaped sternebra-5 in group 4. This was attributed to delayed ossification, related to maternal toxicity. A NOAEL (maternal, embryotoxicity) of 30 mg/kg bw/day was derived from this study and is predicted for Chiguard 5599 for pre-natal developmental toxicity.

3.3.2 Effect of structural differences between target and source chemical

The target substance predominantly contains the C8 alkyl chain variant (91.24%) while the source substance contains ≥40% of CAS No. 104810-48-2 and ≥30% of CAS No. 104810-47-1. The structural differences consist of an alkyl chain which is C7-C9 in Chiguard 5599 and in Tinuvin 1130 diethyl ether branched chains (C6-C7). There is also an esterification reaction combining the two components (CAS No. 104810-48-2) to form CAS No. 104810-47-1 but the main functional groups are the same. These side chain differences are chemically simple structures and are not expected to affect the prediction of pre-natal developmental toxicity for the target substance. In the data matrix (Table 3), it can be noted that the comparison of effects for all other properties (other than the predicted property) is consistent and shows a similar toxicity profile. The only exception is skin sensitisation. In the guinea pig maximization test, the target substance Chiguard 5599 is not a skin sensitizer while the source substance Tinuvin 1130 is a skin sensitizer. Both Chiguard 5599 and Tinuvin 1130 (CAS No. 104810-48-2 and CAS No. 104810-47-1) were profiled in the OECD Toolbox 3.3.0. From Figure 1 we can see there were alerts for the parent target substance and simulated skin metabolites but the in vivo data indicates it is negative. For the source substance there is a nucleophilic substitution alert (SN2 mechanism for allyl acetate & derivatives) for the parent CAS No. 104810-47-1 and 2 simulated skin metabolites. It is likely that the repeated (OCH2CH2)6-7 groups in CAS No. 104810-47-1, which are not present in Chiguard 5599 are responsible for the alert and thus the skin sensitisation properties of Tinuvin 1130. So, apart from the structural difference that contributes to the difference in skin sensitisation properties, both Chiguard 5599 and Tinuvin 1130 are expected to demonstrate the same effects.

3.3.3 Classification and labelling

For the 28-day repeated dose toxicity study for Chiguard 5599, the full study report was not available but the harmonised classification in the ECHA C&L inventory (checked 15-07-15) does not indicate that a STOT-RE classification is warranted. Based on available data in the IUCLID dossier, the target substance is not classified according to the CLP Regulation (1272/2008) for any human health hazard.

In ECHA’s C&L inventory database, the harmonized classification and labelling for Tinuvin 1130 based on the CLP Regulation criteria indicate the following classification for human health hazards: Skin Sensitisation 1. The impurity in the source substance, Tinuvin 1130 is identified and the typical concentration is 10%. In ECHAs C&L inventory, 1910 notifiers indicate that the impurity is not classified (checked on 15-07-15). Therefore, the impurity is not expected to contribute to any effects that are noted for the source substance.

Based on the read-across pre-natal developmental study presented for the source substance, Tinuvin 1130, the conclusion for classification of reproductive toxicity for Chiguard 5599, according to the CLP Regulation, is not classified, when the criteria outlined in Annex I of 1272/2008/EC is applied.

4 Conclusion

The structural similarities between the source and the target substances and estimated similar toxicokinetic routes presented above support the read-across hypothesis that the target and sources substances have the same type of effects. Adequate, reliable and available scientific information indicates that using the source substance for read across to the target substance is acceptable.

Therefore, based on the considerations above, it can be concluded that the pre-natal developmental toxicity study conducted in rats with Tinuvin 1130 is likely to predict the properties of Chiguard 5599 and are considered as adequate to fulfill the information requirement of Annex VIII, 8.7.1.

5 Data matrix

A summary of key data for the target substance and source substance is presented in Table 3 (see attached).