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EC number: 232-800-2 | CAS number: 9025-57-4
The acute oral and inhalation toxicity of xylanase has been tested. The acute oral toxicity test and the acute inhalation toxicity test were short-term toxicity tests conducted according to OECD guidelines, and in compliance with GLP. No acute dermal toxicity test was conducted. The conclusion of the performed studies was that xylanase is non-toxic by acute oral and inhalation exposure (GHS Toxicity category V and IV, respectively). Based on weight of evidence, xylanase does not exert any acute dermal toxicity under foreseeable realistic exposures for both workers and consumers.
The objective of this study was to assess the acute toxicity of Xylanase when administered as a single oral dose to six rats followed by an observation period of 14 days. The purpose of the study was to satisfy regulatory demands because the enzyme is used for production of food in China.
The study was conducted in accordance with the OECD Guideline No 423, “Acute Oral Toxicity – Acute Toxic Class method”. The design of the limit test was used. The test item was supplied as a brown liquid ready to use. The dose volume administered was 20.6 mL/kg body weight corresponding to 2102 mg/kg body weight, based on the Total Organic Solids (TOS) content of the test substance.
No mortality or clinical signs were observed after treatment and the overall body weight gain during the study was considered to be normal. The necropsy revealed no abnormalities.
In conclusion, no signs of toxicity were observed among the rats treated with a single oral dose of 2102 mg TOS/kg body weight, which was the highest possible dose at dose volume 20.6 mL/kg, using the undiluted test item.
The present study was performed in rats, in accordance with GLP and in compliance with EEC, OECD and US EPA (Health Effects Test Guidelines, OPPTS 870, 1300, Acute Inhalation Toxicity, 5 August 1998) and JMAFF test guidelines for acute inhalation studies. One control group and one test group each consisting of 5 females and 5 males were included.
The animals in the test group were exposed by snout-only exposure for 4 hours to air containing a liquid droplet aerosol generated from the test substance, Xylanase, PPQ 6460, at a concentration of 4.95 mg/L. In total 85% of the particles of Xylanase, PPQ 6460, were < 7 µm and had a mass median aerodynamic diameter of 3.1 µm.
The animals were observed during exposure, for two hours after the exposure and daily during the 14-day observation period. After the observation period, the animals were sacrificed and examined pathologically.
During exposure exaggerated breathing was noted in all animals. The exaggerated breathing persisted in 1 test female up to 2 hours post exposure. Fur/skin soiled with excreta was observed in all test and control rats immediately following exposure, persisting in 1 control male up to 2 hours post exposure. Wet fur (whole body) was noted in a proportion of control and test rats immediately following exposure, persisting up to 1-hour post exposure. Brown staining on the head was seen on a proportion of control and test rats up to 2 hours after exposure. These were temporary signs and were considered to be associated with the tube restraint for inhalation exposure.
The mean bodyweight gain for male and female test rats were 81 g and 20 g compared with 95 g and 23 g for control male and female rats during the 14-days observation period respectively.
In conclusion, as there were no unscheduled deaths or evidence of a toxic response following exposure of rats for 4 hours to a droplet aerosol generated from Xylanase, PPQ 6460 at a chamber concentration of 4.95 mg/L in air, the LC50 for Xylanase is in excess of 4.95 mg/L based on test material.
The acute oral and inhalation toxicity of xylanase have been tested. The acute oral toxicity test and the acute inhalation toxicity test were short-term toxicity tests conducted according to OECD guidelines, and in compliance with GLP.
No acute dermal toxicity test was conducted. The overall conclusion of the performed studies was that xylanase does not exert any acute oral or inhalation toxicity. Based on physico-chemical properties and data from other enzymes, xylanase is not expected to present any hazard with regard to acute dermal toxicity under foreseeable realistic exposures for both workers and consumers.
Acute Oral Toxicity: No signs of toxicity were observed among the rats treated with a single oral dose of 2102 mg/kg body weight (expressed in mg total organic solids).
Acute Inhalation Toxicity: No clinical effects related to the test compound were observed and no animals died. In conclusion, the LC50 was therefore considered to be greater than 4.95 mg/L (of the test item as received).
Due to the fact that enzymes are respiratory allergens, DMEL (Derived Minimum Effect Level) values have to be established to ensure that enzymes can be used safely (ref. 3 below). Appropriate exposure limits have been being established to protect consumers, professionals and workers (ref. 3 below). Respiratory allergy is considered the most sensitive endpoint for enzymes. However, when the exposure limit recommendations are followed, this will ensure that exposure levels are low and without any toxicological relevance. Commonly, occupational exposure limit (OEL) values for workers are between 40-60 ng enzyme protein/m3 (8 hour time-weighted average values) in EU countries. More than 30 studies on acute inhalation toxicity in rodents revealed that for the majority of enzymes, no harmful effect could be detected at concentrations up to several mg/L air or g/m3 representing the highest possible concentrations administered and equivalent to nuisance dust levels. In the few cases where LC50 values could be established, the values were more than a factor of 10^6 above the actual OEL value, indicating that the concentrations normally used in acute inhalation toxicity studies are irrelevant to all known exposure scenarios.
The industry has further taken measures to minimize occupational exposure. Workers safety is assured through proper work practices, effective cleaning, engineering controls, and use of personal protective equipment (ref. 5).
Acute Dermal Toxicity: No acute dermal toxicity study has been conducted. However, in general enzymes are of very low toxicity due to ready biodegradability and very low bioavailability. Investigations of percutaneous absorption of peptides, proteins and other molecules of large size revealed that percutaneous absorption of proteins is extremely low and of no toxicological relevance (ref. 1, 2, 4). This is further supported by the physico-chemical data, as xylanases are proteins with molecular weight above 7,700 D, with a low logPow value, indicating that it has no bioaccumulation potential and can be anticipated to be readily biodegraded. Thus, systemic exposure following enzyme exposure at occupational exposure levels is without toxicological significance.
In traditional acute dermal toxicity testing, mortality has been the endpoint. However, because enzymes show very low toxicity, extremely high doses that are far above human exposure levels typically have been applied. Therefore, acute dermal toxicity studies are not considered to provide appropriate knowledge and are as such not a relevant test system for enzymes.
Systemic exposure by the dermal route is unlikely based upon the existing toxicokinetic knowledge of enzymes, which due to their relatively large molecular weight, are not expected to be absorbed through the skin. Therefore, it can be assumed with high certainty that non-protease enzymes do not exert any acute dermal toxicity.
Data waivers will further be established through exposure scenarios, i.e. no significant dermal exposure to consumers and professionals due to the toxicologically insignificant enzyme concentrations in end products and in the case of workers due to occupational hygiene measures associated with the prevention of respiratory allergy which includes protective clothing.
In conclusion, toxicokinetic data together with evidence from animal studies and historical human experience derived from the use of detergent enzymes for decades confirm that exposure to technical enzymes will not result in any toxicologically relevant uptake by dermal route. Acute systemic exposure to a toxicologically significant amount of enzymes by this route can therefore be excluded and will further be prohibited by the obligatory setting of a DMEL value for enzymes, resulting in negligible exposure to enzymes (ref. 3).
1) Basketter,D.A., English,J.S., Wakelin,S.H., and White,I.R. (2008) Enzymes, detergents and skin: facts and fantasies. British journal of dermatology 158, 1177-1181
2) Pease,C.K.S., White,I.R., and Basketter,D.A. (2002) Skin as a route of exposure to protein allergens. Clinical and experimental dermatology 27, 296-300
3) D.A. Basketter, C. Broekhuizen, M. Fieldsend, S. Kirkwood, R. Mascarenhas, K. Maurer, C. Pedersen, C. Rodriguez & H.E. Schiff: Defining occupational and consumer exposure limits for enzyme protein respiratory allergens under REACH, Toxicology 268: 165-170, 2010.
4) Basketter D., Berg N., Broekhuizen C., Fieldsend M., Kirkwood S., Kluin C., Mathieu S. and Rodriguez C.Enzymes in Cleaning Products: An Overview of Toxicological Properties and Risk Assessment/Management. 2012. Reg. Toxicol. Pharmacol, 64/1: 117-123
5) US SDA. Risk assessment guidance for enzyme-containing products. 2005. Washington, Soap and Detergent Association
Based on the low acute oral toxicity of xylanase, the low likelihood of absorption of enzymes through the skin due to the physico-chemical properties of the enzyme and the low exposure to enzymes by inhalation enforced by the respiratory allergy exposure limits, xylanase should not be classified.
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