Lexikon
acute oral toxicity refers to those adverse effects occurring following oral administration of a single dose of a substance, or multiple doses given within 24 hours.
acute systemic toxicity testing is the estimation of the human hazard potential of a substance by determining its systemic toxicity in a test system (currently animals) following an acute exposure. Its assessment has traditionally been based on the median lethal dose (LD50) value - an estimate of the dose of a test substance that kills 50% of the test animals. For a substance to have systemic toxic effects it must be absorbed by the body and distributed by the circulation to sites in the body where it exerts toxic effects. The liver may transform a circulating drug or chemical to another form (biotransformation), and this new metabolite may be the one causing the observed toxicity.
Acute systemic toxicity is assessed following oral, dermal, and/or inhalation exposure(s) - depending upon the anticipated routes of human exposure to the substance. The Globally Harmonized System (GHS), which is scheduled for implementation in 2008, defines acute toxicity as "those adverse effects occurring following oral or dermal administration of a single dose of a substance, or multiple doses given within 24 hours, or an inhalation exposure of 4 hours"
Sources:
UNECE, 2004, p. 109.
http://www.alttox.org/ttrc/toxicity-tests/acute/
short term toxicity. The adverse effects of chemical substances which result either from a single exposure or from multiple exposures in a short space of time.
In animal testings "acute" is the toxicity, when the adverse effects occurs within 14 days of the administration of the substance. In ecotoxicity testings acute toxicity is defined as a period of time shorter, than the generation time of the testorganism. The endpoints used for the quantitative characterisation of acute toxicity are: EC50, LC50 or ED50 and LD50 values.
Acute toxicity is distinguished from chronic toxicity, which describes the adverse health effects from repeated exposures, often at lower levels, to a substance over a longer time period months or years.
acute toxicity concerns the adverse effects, which may result from a single exposure or multiple exposures within 24 hours to a substance in toxicity tests. Exposure relates to the oral, dermal or inhalation routes. Assessment of the acute toxic potential of a chemical is necessary to determine the adverse health effects that might occur following accidental or deliberate short-term exposure: the types of toxic effects, their time of onset, duration and severity, the dose-response relationships, and the sex differences in response. The investigated damages can be clinical signs of toxicity, abnormal body weight changes, and/or pathological changes in organs and tissues, which in some cases may result in death.
Source: REACH
in Annexes VII and VIII to Directive 79/831/EEC, methods for the determination of the ecotoxicity of chemical substances are enlisted. The methods are based on those recognized and recommended by competent international bodies (in particular OECD).
General introduction
1 acute toxicity for fish
2 acute toxicity for Daphnia
3 algal inhibition test
4 biodegradation: determination of the "ready" biodegradability
4-a dissolved organic carbon (doc) die-away test
4-b modified oecd screening test
4-c carbon dioxide evolution test
4-d manometric respirometry test
4-e closed bottle test
4-f miti test
5 degradation : biochemical oxygen demand
6 degradation: chemical oxygen demand
7 degradation: abiotic degradation: hydrolysis as a function of ph
8 toxicity for earthworms : artificial soil test
9 biodegradation: Zahn−Wellens test
10 biodegradation: activated sludge simulation test
11 biodegradation: activated sludge respiration inhibition test
12 biodegradation: modified scas test
13 bioconcentration: flow-through fish test
14 fish juvenile growth test
15 fish, short-term toxicity test on embryo and sac-fry stages
16 honeybees, acute oral toxicity test
17 honeybees, acute contact toxicity test
18 adsorption/desorption using a batch equilibrium method
19 estimation of the adsorption coefficient (koc) on soil and on sewage sludge using high performance liquid chromatography (hplc)
20 Daphnia magna reproduction test
21 soil microorganisms: nitrogen transformation test
22 soil microorganisms: carbon transformation test
23 aerobic and anaerobic transformation in soil
24 aerobic and anaerobic transformation in aquatic sediment systems
in Annexes VII and VIII to Directive 79/831/EEC, methods for the determination of the toxicity of chemical substances are enlisted. The methods are based on those recognized and recommended by competent international bodies (in particular OECD).
1 general introduction
1bis acute oral toxicity - fixed dose procedure
1tris acute oral toxicity - acute toxic class method
2 acute toxicity (inhalation)
3 acute toxicity (dermal)
4 acute toxicity: dermal irritation/corrosion
5 acute toxicity: eye irritation/corrosion
6 skin sensitisation
7 repeated dose (28 days) toxicity (oral)
8 repeated dose (28 days) toxicity (inhalation)
9 repeated dose (28 days) toxicity (dermal)
10 mutagenicity − in vitro mammalian chromosome aberration test)
11 mutagenicity − in vivo mammalian bone-marrow chromosome aberration test
12 mutagenicity mammalian erythrocyte micronucleus test
13/14 mutagenicity − reverse mutation test using bacteria
15 gene mutation − Saccharomyces cerevisae
16 mitotic recombination − Saccharomyces cerevisae
17 mutagenicity − in vitro mammalian cell gene mutation test
18 dna damage and repair − unscheduled dna synthesis − mammalian cells in vitro
19 sister chromatid exchange assay in vitro
20 sex-linked recessive lethal test in Drosophila melanogaster
21 in vitro mammalian cell transformation test
22 rodent dominant lethal test
23 mammalian spermatogonial chromosome aberration test
24 mouse spot test
25 mouse heritable translocation
26 sub-chronic oral toxicity test. Repeated dose 90-day toxicity study in rodents
27 sub-chronic oral toxicity test: repeated dose 90-day toxicity study in non-rodents
28 sub-chronic dermal toxicity test: 90-day repeated dermal dose study using rodent species
29 sub-chronic inhalation toxicity test: 90-day repeated inhalation dose study using rodent species
30 chronic toxicity test
31 teratogenicity test rodent and non-rodent
32 carcinogenicity test
33 combined chronic toxicity/carcinogenicity test
34 one-generation reproduction toxicity test
35 two generation reproduction toxicity test
36 toxicokinetics
37 delayed neurotoxicity of organophosphorus substances following acute exposure
38 delayed neurotoxicity of organophosphorus substances 28 day repeated dose study
39 unscheduled dna synthesis (uds) test with mammalian liver cells in vivo
40 skin corrosion (in vitro)
41 phototoxicity − in vitro 3t3 nru phototoxicity test
42 skin sensitisation: local lymph node assay
43 neurotoxicity study in rodents
ECOTOXICITY TESTING METHODS TO BE USED BY THE REACH REGULATION are enlisted in the COUNCIL REGULATION (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
(1) Pursuant to Regulation (EC) No 1907/2006, test methods are to be adopted at Community level for the purposes of tests on substances where such tests are required to generate information on intrinsic properties of substances.
(2) Council Directive 67/548/EEC of 27 June 1967 on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances laid down, in Annex V, methods for the determination of the physico-chemical properties, toxicity and ecotoxicity of substances and preparations. Annex V to Directive 67/548/EEC has been deleted by Directive 2006/121/EC of the European Parliament and of the Council with effect from 1 June 2008.
(3) The test methods contained in Annex V to Directive 67/ 548/EEC should be incorporated into this Regulation.
(4) This Regulation does not exclude the use of other test methods, provided that their use is in accordance with Article 13(3) of Regulation 1907/2006.
(5) The principles of replacement, reduction and refinement of the use of animals in procedures should be fully taken into account in the design of the test methods, in particular when appropriate validated methods become available to replace, reduce or refine animal testing.
(6) The provisions of this Regulation are in accordance with the opinion of the Committee established under Article 133 of Regulation (EC) No 1907/2006
Article 1: The test methods to be applied for the purposes of Regulation 1907/2006/EC are set out in the Annex to this Regulation.
Article 2: The Commission shall review, where appropriate, the test methods contained in this Regulation with a view to replacing, reducing or refining testing on vertebrate animals.
Article 3: All references to Annex V to Directive 67/548/EEC shall be construed as references to this Regulation.
Article 4: This Regulation shall enter into force on the day following its publication in the Official Journal of the European Union.
It shall apply from 1 June 2008.
LIST OF METHODS FOR THE DETERMINATION OF ECOTOXICITY
C.1. Acute toxicity for fish
C.2. Daphnia sp. Acute immobilisation test
C.3. Algal inhibition test
C.4. Determination of ‘ready’ biodegradability
Part i. General considerations
Part ii. Doc die-away test (method C.4-a)
Part iii. Modified oecd screening test (method C.4-b)
Part iv. Co2 evolution test (method C.4-c)
Part v. Manometric respirometry test (method C.4-d)
Part vi. Closed bottle test (method C.4-e)
Part vii. M.I.T.I. Test (method C.4-f)
C.5. Degradation — biochemical oxygen demand
C.6. Degradation — chemical oxygen demand
C.7. Degradation — abiotic degradation: hydrolysis as a function of ph
C.8. Toxicity for earthworms
C.9. Biodegradation — Zahn-Wellens test
C.10. Biodegradation — activated sludge simulation tests
C.11. Biodegradation — activated sludge respiration inhibition
C.12. Biodegradation — modified SCAS test
C.13. Bioconcentration: flow-through fish test
C.14. Fish juvenile growth test
C.15. Fish, short-term toxicity test on embryo and sac-fry stages
C.16. Honeybees — acute oral toxicity test
C.17. Honeybees — acute contact toxicity test
C.18. Adsorption/desorption using a batch equilibrium method
C.19. Estimation of the adsorption coefficient (koc) on soil and on sewage sludge using high performance liquid chromatography (HPLC)
C.20. Daphnia magna reproduction test
C.21. Soil microorganisms: nitrogen transformation test
C.22. Soil microorganisms: carbon transformation test
C.23. Aerobic and anaerobic transformation in soil
C.24. Aerobic and anaerobic transformation in aquatic sediment systems
the results of environmental toxicology are mainly used for the prediction of hazard and risk of single chemical substances or contaminated environment at local, regional and global scale. Their important role is supporting decision making in environmental management and policy by setting risk based priorities, establishing environmental quality criteria, to design monitoring systems, to select risk reduction measures, to establish land use specific target values and so on. Environmnetal toxicity results are suitable for direct decision making, when building decision only on the effects.
evident toxicity is a general term in toxicity tests describing clear signs of toxicity following the administration of test.
neurotoxicology is the study of the adverse effects of chemical, biological, and certain physical agents on the nervous system and/or behavior during development and in maturity. Many common substances are neurotoxic, including lead, mercury, some pesticides, and ethanol.
Neurotoxicity testing is used to identify potential neurotoxic substances. Neurotoxicity is a major toxicity endpoint that must be evaluated for many regulatory applications. Sometimes neurotoxicity testing is considered as a component of target organ toxicity; the central nervous system (CNS) being one of the major target organ systems. In utero exposure to chemicals and drugs can also exert an adverse effect on the development of the nervous system, which is called developmental neurotoxicity (DNT).
Like other target organ toxicities, neurotoxicity can result from different types of exposure to a substance; the major routes of exposure are oral, dermal, or inhalation. Neurotoxicity may be observed after a single (acute) dose or after repeated (chronic) dosing.
Source: http://alttox.org/ttrc/toxicity-tests/neurotoxicity/
the repeated dose toxicity comprises the general toxicological effects occurring as a result of repeated daily exposure to a substance for a part of the expected lifespan (sub-acute or sub-chronic exposure) or for the major part of the lifespan (chronic exposure).
These general toxicological effects include effects on body weight and/or body weight gain, absolute and/or relative organ and tissue weights, alterations in clinical chemistry, urinalysis and/or haematological parameters, functional disturbances in the nervous system as well as in organs and tissues in general, and pathological alterations in organs and tissues as examined macroscopically and microscopically. Besides this information on possible adverse general toxicological effects, repeated dose toxicity studies may also provide other information on e.g. reproductive toxicity or carcinogenicity or may identify specific manifestations of toxicity such as e.g., neurotoxicity, immunotoxicity, endocrine-mediated effects...
The objectives of assessing repeated dose toxicity are to evaluate:
- whether repeated exposure of humans to a substance has been associated with adverse toxicological effects; these human studies potentially may also identify populations that have higher susceptibility;
- whether repeated administration of a substance to experimental animals causes adverse toxicological effects; effects that are predictive of possible adverse human health effects;
- the target organs, the potential cumulative effects and the reversibility of the adverse toxicological effects;
- the dose-response relationship and the threshold for any of the adverse toxicological effects observed in the repeated dose toxicity studies;
Source: REACH
reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring. As a short name "reprotox" is also used. Those chemical substances which may cause reproductive toxicity are reprotoxic substances.
Reproductive Toxicity is differentiated into:
– adverse effects on sexual function and fertility;
– adverse effects on development;
– effects on or via lactation. (REACH)
Animal tests include evaluating the effects of prenatal exposure on pregnant animals and their offspring [OECD Test Guideline (TG) 414]. This test is usually performed with female rats and rabbits. The test substance is administered orally, the pregnant animals are killed just prior to delivery, and the fetuses are examined for toxic effects. A one-generation reproduction toxicity study (OECD TG 415) in rats or mice is used to evaluate toxic effects on male and female reproduction. Males and females are dosed orally before mating, and females during pregnancy. A two-generation reproduction toxicity study (OECD TG 416) continues dosing with the test substance to the first generation offspring. OECD TG 421 (Reproductive/Developmental Toxicity Screening Assay) uses male and female rats with the test substance administered orally for 4-9 weeks. Pathological effects are determined by daily observation, necropsy, and microscopic histopathology.
The Organisation for Economic Cooperation and Development (OECD) adopted two draft proposals for new reproductive/developmental toxicity TGs in October 2007. Draft Proposal 426,
An ICCVAM-NICEATM workshop reviewed the Frog Embryo Teratogenesis Assay: Xenopus (FETAX) as a potential alternative for assessing developmental toxicants. The method was deemed not ready for validation, so recommendations were made for its continued development.
The ECVAM Scientific Advisory Committee (ESAC) "endorsed three in vitro methods for embryotoxicity testing as scientifically validated" (ESAC Statements, May 1, 2002):
- Embryonic stem cell test for embryotoxicity
- Micromass embryotoxicity assay
- Whole rat embryo embryotoxicity assay
The ESAC recommended these in vitro methods as ready for regulatory acceptance but acknowledged they cannot replace the animal tests. However, when used as part of a testing strategy, they could contribute to reducing animal use. (Source: http://www.alttox.org/ttrc/toxicity-tests/repro-dev-tox/)
reproductive toxicity is of obvious high concern because the continuance of the human species is dependent on the integrity of the reproductive cycle. It is characterised by multiple diverse endpoints, such as impairment of male and female reproductive functions or capacity (fertility), induction of non-heritable harmful effects on the progeny (developmental toxicity) and effects on or mediated via lactation.
The objectives of assessing reproductive toxicity are to establish:
- whether exposure of humans to the substance of interest has been associated with reproductive toxicity;
- whether, on the basis of information other than human data, it can be predicted that the substance will cause reproductive toxicity in humans;
- whether the pregnant female is potentially more susceptible to general toxicity;
- the dose-response relationship for any adverse effects on reproduction.
Source: REACH
the testing of physico-chemical characteristics of chemical substances is regulated by the COUNCIL REGULATION (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).
(1) Pursuant to Regulation (EC) No 1907/2006, test methods are to be adopted at Community level for the purposes of tests on substances where such tests are required to generate information on intrinsic properties of substances.
(2) Council Directive 67/548/EEC of 27 June 1967 on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances laid down, in Annex V, methods for the determination of the physico-chemical properties, toxicity and ecotoxicity of substances and preparations. Annex V to Directive 67/548/EEC has been deleted by Directive 2006/121/EC of the European Parliament and of the Council with effect from 1 June 2008.
(3) The test methods contained in Annex V to Directive 67/ 548/EEC should be incorporated into this Regulation.
(4) This Regulation does not exclude the use of other test methods, provided that their use is in accordance with Article 13(3) of Regulation 1907/2006.
(5) The principles of replacement, reduction and refinement of the use of animals in procedures should be fully taken into account in the design of the test methods, in particular when appropriate validated methods become available to replace, reduce or refine animal testing.
(6) The provisions of this Regulation are in accordance with the opinion of the Committee established under Article 133 of Regulation (EC) No 1907/2006
Article 1: The test methods to be applied for the purposes of Regulation 1907/2006/EC are set out in the Annex to this Regulation.
Article 2: The Commission shall review, where appropriate, the test methods contained in this Regulation with a view to replacing, reducing or refining testing on vertebrate animals.
Article 3: All references to Annex V to Directive 67/548/EEC shall be construed as references to this Regulation.
Article 4: This Regulation shall enter into force on the day following its publication in the Official Journal of the European Union.
It shall apply from 1 June 2008.
LIST OF METHODS FOR THE DETERMINATION OF TOXICITY
B.1 bis. Acute oral toxicity – fixed dose procedure
B.1 tris. Acute oral toxicity – acute toxic class method
B.2. Acute toxicity (inhalation)
B.3. Acute toxicity (dermal)
B.4. Acute toxicity: dermal irritation/corrosion
B.5. Acute toxicity: eye irritation/corrosion
B.6. Skin sensitisation
B.7. Repeated dose (28 days) toxicity (oral)
B.8. Repeated dose (28 days) toxicity (inhalation)
B.9. Repeated dose (28 days) toxicity (dermal)
B.10. Mutagenicity – in vitro mammalian chromosome aberration test
B.11. Mutagenicity – in vivo mammalian bone marrow chromosome aberration test
B.12. Mutagenicity – in vivo mammalian erythrocyte micronucleus test
B.13/14. Mutagenicity: reverse mutation test using bacteria
B.15. Mutagenicity testing and screening for carcinogenicity gene mutation – saccharomyces cerevisiae
B.16. Mitotic recombination – saccharomyces cerevisiae
B.17. Mutagenicity – in vitro mammalian cell gene mutation test
B.18. Dna damage and repair – unscheduled dna synthesis – mammalian cells in vitro
B.19. Sister chromatid exchange assay in vitro
B.20. Sex-linked recessive lethal test in drosophila melanogaster
B.21. In vitro mammalian cell transformation tests
B.22. Rodent dominant lethal test
B.23. Mammalian spermatogonial chromosome aberration test
B.24. Mouse spot test
B.25. Mouse heritable translocation
B.26. Sub-chronic oral toxicity test repeated dose 90-day oral toxicity study in rodents
B.27. Sub-chronic oral toxicity test repeated dose 90-day oral toxicity study in nonrodents
B.28. Sub-chronic dermal toxicity study 90-day repeated dermal dose study using
Rodent species
B.29. Sub-chronic inhalation toxicity study 90-day repeated inhalation dose studusing rodent species
B.30. Chronic toxicity test
B.31. Prenatal developmental toxicity study
B.32. Carcinogenicity test
B.33. Combined chronic toxicity/carcinogenicity test
B.34. One-generation reproduction toxicity test
B.35. Two-generation reproduction toxicity study
B.36. Toxicokinetics
B.37. Delayed neurotoxicity of organophosphorus substances following acute exposure
B.38. Delayed neurotoxicity of organophosphorus substances 28 day repeated dose study
B.39. Unscheduled dna synthesis (uds) test with mammalian liver cells in vivo
B.40. In vitro skin corrosion: transcutaneous electrical resistance test (ter)
B.40 bis. In vitro skin corrosion: human skin model test
B.41. In vitro 3T3 NRU phototoxicity test
B.42. Skin sensitisation: local lymph node assay
B.43. Neurotoxicity study in rodents
B.44. Skin absorption: in vivo method
B.45. Skin absorption: in vitro method