Reaction product of 2-hydroxybenzoic acid, styrene and oxozinc

Endpoint summary

Description of key information

Summary

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance Reaction product of 2-hydroxybenzoic acid, styrene and oxozinc is an organic UVCB constituent solid with a purity of 100% (w/w).

A full ADME toxicokinetic study in the rat is not available. In vivo studies covering the oral route (acute oral toxicity study in rats, 28-day repeated dose oral toxicity study in rats and reproduction/developmental toxicity screening test in rats), the dermal route (acute dermal toxicity study in rats, in vivo skin sensitisation test and in vivo skin irritation test) and the inhalation route (acute inhalation toxicity study) are available. The toxicokinetic analysis is based on the physicochemical and in vivo toxicological data. Further details on endpoints are available in the IUCLID 6 registration dossier.

Based on the physicochemical data and available in vivo toxicological data, absorption of Reaction product of 2-hydroxybenzoic acid, styrene and oxozinc is expected to be moderate via the oral route, low via the dermal route and negligible via the inhalation route. The target organ for toxicity is the reproductive organs in males and females, with accumulation expected during repeated exposure.

The absorption rates of 50% (oral), 50% (dermal) and 50% (inhalation) are accepted for chemical risk assessment purposes.

 

1.Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of Reaction product of 2-hydroxybenzoic acid, styrene and oxozinc in the body.

 

Absorption - oral

The molecular weight of Reaction product of 2-hydroxybenzoic acid, styrene and oxozinc (547.93-756.23 g/mol, two main constituents considered) is not in the range for favorable oral absorption (<500 g/mol). The log Kow of the substance is 2.78 - 5.64 at 25°C which can be considered as moderate, favorable for passive diffusion. The water solubility in water is 74.7 mg/L at 20°C as moderate for absorption. Oral absorption is expected to be low but if absorption does occur, it is likely via the lymphatic system through micellular solubilisation, based on the lipophilicity and water solubility.

 

Absorption – dermal

The molecular weight of Reaction product of 2-hydroxybenzoic acid, styrene and oxozinc (547.93-756.23 g/mol, two main constituents considered) is in the range for unfavourable oral absorption (>500 g/mol). As the water solubility of Reaction product of 2-hydroxybenzoic acid, styrene and oxozinc is 74.7 mg/L at 20°C, low to moderate dermal uptake is expected. The moderate log Pow value indicates slow transfer to the epidermis and entry into systemic circulation; The chemical structure of the substance contains metal ion as Zn²⁺ and ionized products do not pass through easily. Overall the molecular weight and its structure, log Pow and water solubility indicate that dermal absorption of Reaction product of 2-hydroxybenzoic acid, styrene and oxozinc is likely to be low.

 

Absorption – inhalation

The particle size distribution report for Reaction product of 2-hydroxybenzoic acid, styrene and oxozinc indicates more than 90 % of the test item was found to be bigger than 125 μm. This indicates that <10% of the particles are available in the inhalable fractions of air (<100 μm) and therefore it is a considered to have no or low dustiness. Exposure via the inhalation route is expected to be negligible.

2. Information from other studies in the dossier

Absorption – oral

 

Acute oral toxicity study in rats

In the acute oral toxicity study according to OECD TG 401, 10/sex/group of male and female rats were administrated with Reaction product of 2-hydroxybenzoic acid, styrene and oxozinc (5000 mg/kg/bw) by oral gavage. No toxic signs were observed after application of test item, and no death occurred within two weeks. No pathological changes were observed at necropsy. Oral LD50 was greater than 5000 mg/kg bw for both male and female Wistar rats.

 

28-day repeated oral toxicity study in rats

In an 28-day toxicity study conducted under GLP compliance according to OECD TG 407, the test item was administered orally (by gavage) to Hsd.Brl.Han: Wistar rats (n=5/sex/group) once a day at 0, 50, 20 and 5 mg/kg bw/day doses corresponding to concentrations of 0, 10, 4 and 1 mg/mL, applied in a dose volume of 5 mL/kg bw for 28 days.

No mortality occurred during the observation period. Toxic signs related to the test item were not found at any dose level at the daily and detailed weekly clinical observations and in the course of functional observation battery.A test item influence on the body weight development was noted for male and female animals of 50 and 20 mg/kg bw/day groups. The reduced body weight gain resulted in a less body weight at 50 and 20 mg/kg bw/day from Day 7 and 14, respectively, in male animals and from Day 7 in female animals up to the end of the treatment period. The daily mean food consumption was slightly reduced in male and female animals at 50 mg/kg bw/day and in female animals at 20 mg/kg bw/day.Clinical pathology examinations did not reveal any pathologic changes in the examined hematology, blood coagulation or clinical chemistry parameters. Test item influence on the male genital organs was detected at the necropsy. The testes, epididymides, prostate and seminal vesicles with coagulating gland were smaller than normal in male animals of 50 mg/kg bw/day group. Test item induced macroscopic changes in the male genital organs and accessory sex organs were supported by the organ weight evaluation. The weights of testes, epididymides, prostate and seminal vesicles with coagulating gland (as a whole) were statistically significantly less with respect to the control at 50 mg/kg bw/day dose level.Histological examination – in full compliance with the results of the necropsy and organ weight examinations – revealed decreased secretion activity in the ductuli of seminal vesicles and prostate, decreased intensity of spermatogenesis in the testes, lack of the mature spermatozoa in the testes and epididymides in male animals of the 50 mg/kg bw/day group.

In conclusion, Reaction Product of 2-Hydroxybenzoic Acid, Styrene and Oxozinc caused reduction in body weight development and food consumption (male and female), macroscopic and weight changes accompanied by histological alterations in male genital organs and accessory sex organs in Hsd.Brl.Han: Wistar rats after 28-days oral (gavage) administration at 50 mg/kg bw/day.At 20 mg/kg bw/day, test item influence was observed in the reduced body weight and body weight gain in male and female animals, as well as in the reduced food consumption of female animals.In the 5 mg/kg bw/day group adverse alterations were observed neither on body weight and food consumption nor on clinical and histopathological parameters.

Based on the findings of this study, the No Observed Adverse Effect Level (NOAEL) was determined as 5 mg/kg bw/day for male and female animals.

 

 

reproduction/developmental toxicity screening test in rats

A reproduction/developmental toxicity screening test was performed to obtain initial information on the possible effects of the test item Reaction Product of 2-Hydroxybenzoic Acid, Styrene and Oxozinc on reproduction and development when administered orally (by gavage) to rats at repeated doses of 40, 15 or 5 mg/kg bw/day compared to control animals according to OECD TG 421 under GLP compliance.

 

There was no mortality in any group (control, 40, 15 or 5 mg/kg bw/day). Test item related clinical signs (pale or cold limbs, decreased activity and piloerection) were observed in male and female animals of 40 mg/kg bw/day group. Pale and cold limbs were also detected in female animals of 15 mg/kg bw/day group.At the detailed weekly observations, the above listed, test item related signs appeared in male (pale or cold limbs, decreased activity and piloerection) and female (pale and cold limbs and piloerection) animals of 40 mg/kg bw/day group. Pale and cold limbs were also detected in female animals of 15 mg/kg bw/day group in the course of weekly clinical observation indicating the cumulative effect of the test item.The body weight development was reduced in male and female animals of 40, 15 and 5 mg/kg bw/day groups with respect to their controls during the entire study. However the changes in 5 mg/kg bw/day group were not considered to be of toxicologically relevant due to the low degree.Test item related effects on the mean daily food consumption were observed in male and female animals in 40, 15 and 5 mg/kg bw/day groups. However the changes in 5 mg/kg bw/day group were not considered to be of toxicologically relevant due to the low degree.Test item related changes were detected in the reproductive performance of male and female animals administered with 40 mg/kg bw/day dose of the test item. The high dose caused infertility of female animals and probably also of male animals.The delivery data of female animals administered with 15 mg/kg bw/day was influenced by the test item as the mean number of total births, live-borns, viable offspring and corpora lutea was significantly less and the mean post-implantation loss was higher in 15 mg/kg bw/day group with respect to the control.Smaller than normal testes, epididymides, seminal vesicles and prostate were noted for some male animals in the 40 mg/kg bw/day dose group supported by the results of organ weight evaluation (testes). Histological examination revealed decreased secretion in the tubules of the seminal vesicles with coagulating gland and prostate, decreased intensity of spermatogenesis in seminiferous tubules in the testes, and lack of mature spermatozoa in the ductuli of epididymides 40 mg/kg bw/day. In the testes, the lack of mature spermatozoa and spermatids was detectable.Involution of corpora lutea and secondary and tertiary follicles was observed in the ovaries of all female animals belonging to the high dose group and in some animal of the 15 mg/kg bw/day group. The complete lack of corpora lutea was detected in several animals in the high dose group.There was no offspring in the 40 mg/kg bw/day group. A test item effect on the offspring development was observed in the less mean offspring weight gain in 15 mg/kg bw/day group between postnatal days 0 and 4.

In conclusion, Reaction Product of 2-Hydroxybenzoic Acid, Styrene and Oxozinc caused clinical signs, reduced body weight development and food consumption (male and female), macroscopic and weight changes accompanied by histological alterations in male genital organs and accessory sex organs, and histological alterations in female genital organ in Hsd.Brl.Han: Wistar rats after repeated dose oral administration at 40 mg/kg bw/day. The high dose caused infertility of female animals and probably also of male animals. At 15 mg/kg bw/day, test item induced clinical signs in female animals, reduced body weight and body weight gain and reduced food consumption in male and female animals. Dam’s delivery data was slightly affected by the test item.The offspring’s body weight development was slightly depressed between postnatal days 0 and 4. In the 5 mg/kg bw/day group, the slight changes in the body weight and food consumption were judged to be toxicologically not relevant.

Based on the findings of this study, the No Observed Adverse Effect Levels (NOAEL) were determined as 5 mg/kg bw/day for male and female rats, 5 mg/kg bw/day for reproductive performance of the male and female rats and 5 mg/kg bw/day for F1 Offspring.

In contrast to the physiochemical data, the in vivo data indicates that moderate oral absorption may be expected. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption rate of 50% is accepted.

 

Absorption – dermal

 

Acute Dermal Toxicity in rats

In an acute dermal toxicity study according to OECD TG 402, 10 male and 10 female Wistar rats were exposed to Reaction Product of 2-Hydroxybenzoic Acid, Styrene and Oxozinc at the dose level of 2000 mg/kg bw for 24 hours and afterwards observed for 14 days after removal of the test item. No clinical toxic signs were observed after application of test item and no death occurred with two weeks. No pathological changes were observed at necropsy. Dermal LD 50 was determined as larger than 2000 mg/kg bw for both male and female Wistar rats.

 

in vivo skin sensitisation test in rats

In a skin sensitization study according to TG OECD 406, 20 male adult puinea pigs were applied with Reaction Product of 2-Hydroxybenzoic Acid, Styrene and Oxozinc. There was no erythema, oedema or other skin changed observed in treated group, the substance was considered as not sensitisation.

 

in vivo skin irritation test in rats

In the acute dermal irritation/Corrosion study according to OECD TG 404, three male adult albino rabbits (New Zealand strain) were applied with 0.5 mL Reaction Product of 2-Hydroxybenzoic Acid, Styrene and Oxozinc for 4 hours by a semi-occlusive exposure. There was no erythema or oedema or any other changed induced, and the score of erythema and oedema were equal to 0. The test item was consiered as non- skin irritation.

 

Together with the physiochemical data, this data indicates that absorption via the dermal route is likely to be low. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

 

Absorption – inhalation

 

Acute Inhalation Toxicity study in rats

In an acute inhalation toxicity study according to OECD TG 403, 10 male and 10 female Wistar rats were exposed to Reaction Product of 2-Hydroxybenzoic Acid, Styrene and Oxozinc at the dose level of 5 mg/L for 5 hours and afterwards observed for 14 days after removal of the substance. No clinical toxic signs were observed after application of test item and no death occurred with two weeks. No pathological changes were observed at necropsy. Inhalation LD50 was determined as larger than 5 mg/L for both male and female Wistar rats.

 

 

Together with the physiochemical data, this data indicates that absorption via the oral route is likely to be low. For chemical safety assessment purposes, an inhalation absorption rate of 50% is accepted.

 

 

Distribution/Metabolism/Excretion

Based on the information provided from the physicochemical data and in vivo studies, the target organ for toxicity is the reproductive organs in males and females, with accumulation expected during repeated exposure. Exposure to the foetus is expected. There is no direct evidence to indicate the route of excretion of the substance. The substance is expected to be excreted in the faeces/urine/air due to its MW.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

50