Search Legislation

Commission Directive 2004/73/ECShow full title

Commission Directive 2004/73/EC of 29 April 2004 adapting to technical progress for the twenty-ninth time Council Directive 67/548/EEC on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances (Text with EEA relevance)

 Help about what version

What Version

 Help about UK-EU Regulation

Legislation originating from the EU

When the UK left the EU, legislation.gov.uk published EU legislation that had been published by the EU up to IP completion day (31 December 2020 11.00 p.m.). On legislation.gov.uk, these items of legislation are kept up-to-date with any amendments made by the UK since then.

Close

This item of legislation originated from the EU

Legislation.gov.uk publishes the UK version. EUR-Lex publishes the EU version. The EU Exit Web Archive holds a snapshot of EUR-Lex’s version from IP completion day (31 December 2020 11.00 p.m.).

Status:

This is the original version (as it was originally adopted).

B.31. PRENATAL DEVELOPMENTAL TOXICITY STUDY

1. METHOD

This method is a replicate of OECD TG 414 (2001).

1.1INTRODUCTION

This method for developmental toxicity testing is designed to provide general information concerning the effects of prenatal exposure on the pregnant test animal and on the developing organism in utero; this may include assessment of maternal effects as well as death, structural abnormalities, or altered growth in the foetus. Functional deficits, although an important part of development, are not an integral part of this test method. They may be tested for in a separate study or as an adjunct to this study using the test method for developmental neurotoxicity. For information on testing for functional deficiencies and other postnatal effects the Test Method for the two-generation reproductive toxicity study and the developmental neurotoxicity study should be consulted as appropriate.

This test method may require specific adaptation in individual cases on the basis of specific knowledge on e.g. physicochemical or toxicological properties of the test substance. Such adaptation is acceptable, when convincing scientific evidence suggests that the adaptation will lead to a more informative test. In such a case, this scientific evidence should be carefully documented in the study report.

1.2DEFINITIONS

Developmental toxicology: the study of adverse effects on the developing organism that may result from exposure prior to conception, during prenatal development, or postnatally to the time of sexual maturation. The major manifestations of developmental toxicity include 1) death of the organism, 2) structural abnormality, 3) altered growth, and 4) functional deficiency. Developmental toxicology was formerly often referred to as teratology.

Adverse effect: any treatment-related alteration from baseline that diminishes an organism's ability to survive, reproduce or adapt to the environment. Concerning developmental toxicology, taken in its widest sense it includes any effect which interferes with normal development of the conceptus, both before and after birth.

Altered growth: an alteration in offspring organ or body weight or size.

Alterations (anomalies): structural alterations in development that include both malformations and variations (28).

Malformation/Major Abnormality: Structural change considered detrimental to the animal (may also be lethal) and is usually rare.

Variation/Minor Abnormality: Structural change considered to have little or no detrimental effect on the animal; may be transient and may occur relatively frequently in the control population.

Conceptus: the sum of derivatives of a fertilised ovum at any stage of development from fertilisation until birth including the extra-embryonic membranes as well as the embryo or foetus.

Implantation (nidation): attachment of the blastocyst to the epithelial lining of the uterus, including its penetration through the uterine epithelium, and its embedding in the endometrium.

Embryo: the early or developing stage of any organism, especially the developing product of fertilisation of an egg after the long axis appears and until all major structures are present.

Embryotoxicity: detrimental to the normal structure, development, growth, and/or viability of an embryo.

Foetus: the unborn offspring in the post-embryonic period.

Foetotoxicity: detrimental to the normal structure, development, growth, and/or viability of a foetus.

Abortion: the premature expulsion from the uterus of the products of conception: of the embryo or of a nonviable foetus.

Resorption: a conceptus which, having implanted in the uterus, subsequently died and is being, or has been resorbed.

Early resorption: evidence of implantation without recognisable embryo/foetus

Late resorption: dead embryo or foetus with external degenerative changes

NOAEL: abbreviation for no-observed-adverse-effect level and is the highest dose or exposure level where no adverse treatment-related findings are observed.

1.3REFERENCE SUBSTANCE

None.

1.4PRINCIPLE OF THE TEST METHOD

Normally, the test substance is administered to pregnant animals at least from implantation to one day prior to the day of scheduled kill, which should be as close as possible to the normal day of delivery without risking loss of data resulting from early delivery. The test method is not intended to examine solely the period of organogenesis, (e.g. days 5-15 in the rodent, and days 6-18 in the rabbit) but also effects from preimplantation, when appropriate, through the entire period of gestation to the day before caesarean section. Shortly before caesarean section, the females are killed, the uterine contents are examined, and the foetuses are evaluated for externally visible anomalies and for soft tissue and skeletal changes.

1.5DESCRIPTION OF THE TEST METHOD
1.5.1 Selection of animal species

It is recommended that testing be performed in the most relevant species, and that laboratory species and strains which are commonly used in prenatal developmental toxicity testing be employed. The preferred rodent species is the rat and the preferred non-rodent species is the rabbit. Justification should be provided if another species is used.

1.5.2 Housing and feeding conditions

The temperature in the experimental animal room should be 22 oC (± 3o) for rodents and 18 o C (± 3o) for rabbits. Although the relative humidity should be at least 30 % and preferably not exceed 70 % other than during room cleaning, the aim should be 50-60 %. Lighting should be artificial, the sequence being 12 hours light, 12 hours dark. For feeding, conventional laboratory diets may be used with an unlimited supply of drinking water. Mating procedures should be carried out in cages suitable for the purpose. While individual housing of mated animals is preferred, group housing in small numbers is also acceptable.

1.5.3 Preparation of the animals

Healthy animals, which have been acclimated to laboratory conditions for at least 5 days and have not been subjected to previous experimental procedures, should be used. The test animals should be characterised as to species, strain, source, sex, weight and/or age. The animals of all test groups should, as nearly as practicable, be of uniform weight and age. Young adult nulliparous female animals should be used at each dose level. The females should be mated with males of the same species and strain, and the mating of siblings should be avoided. For rodents day 0 of gestation is the day on which a vaginal plug and/or sperm are observed; for rabbits day 0 is usually the day of coitus or of artificial insemination, if this technique is used. Mated females should be assigned in an unbiased manner to the control and treatment groups. Cages should be arranged in such a way that possible effects due to cage placement are minimised. Each animal should be assigned a unique identification number. Mated females should be assigned in an unbiased manner to the control and treatment groups, and if the females are mated in batches, the animals in each batch should be evenly distributed across the groups. Similarly, females inseminated by the same male should be evenly distributed across the groups.

1.6PROCEDURE
1.6.1 Number and sex of animals

Each test and control group should contain a sufficient number of females to result in approximately 20 female animals with implantation sites at necropsy. Groups with fewer than 16 animals with implantation sites may be inappropriate. Maternal mortality does not necessarily invalidate the study providing it does not exceed approximately 10 %.

1.6.2 Preparation of doses

If a vehicle or other additive is used to facilitate dosing, consideration should be given to the following characteristics: effects on the absorption, distribution, metabolism, and retention or excretion of the test substance; effects on the chemical properties of the test substance which may alter its toxic characteristics; and effects on the food or water consumption or the nutritional status of the animals. The vehicle should neither be developmentally toxic nor have effects on reproduction.

1.6.3 Dosage

Normally, the test substance should be administered daily from implantation (e.g., day 5 post mating) to the day prior to scheduled caesarean section. If preliminary studies, when available, do not indicate a high potential for preimplantation loss, treatment may be extended to include the entire period of gestation, from mating to the day prior to scheduled kill. It is well known that inappropriate handling or stress during pregnancy can result in prenatal loss. To guard against prenatal loss from factors which are not treatment-related, unnecessary handling of pregnant animals as well as stress from outside factors such as noise should be avoided.

At least three dose levels and a concurrent control should be used. Healthy animals should be assigned in an unbiased manner to the control and treatment groups. The dose levels should be spaced to produce a gradation of toxic effects. Unless limited by the physical/chemical nature or biological properties of the test substance, the highest dose should be chosen with the aim to induce some developmental and/or maternal toxicity (clinical signs or a decrease in body weight) but not death or severe suffering. At least one intermediate dose level should produce minimal observable toxic effects. The lowest dose level should not produce any evidence of either maternal or developmental toxicity. A descending sequence of dose levels should be selected with a view to demonstrating any dosage-related response and no-observed-adverse-effect level (NOAEL). Two- to fourfold intervals are frequently optimal for setting the descending dose levels, and the addition of a fourth test group is often preferable to using very large intervals (e.g. more than a factor of 10) between dosages. Although establishment of a maternal NOAEL is the goal, studies which do not establish such a level may also be acceptable (1).

Dose levels should be selected taking into account any existing toxicity data as well as additional information on metabolism and toxicokinetics of the test substance or related materials. This information will also assist in demonstrating the adequacy of the dosing regimen.

A concurrent control group should be used. This group should be a sham-treated control group or a vehicle-control group if a vehicle is used in administering the test substance. All groups should be administered the same volume of either test substance or vehicle. Animals in the control group(s) should be handled in an identical manner to test group animals. Vehicle control groups should receive the vehicle in the highest amount used (as in the lowest treatment group).

1.6.4 Limit test

If a test at one dose level of at least 1000 mg/kg body weight/day by oral administration, using the procedures described for this study, produces no observable toxicity in either pregnant animals or their progeny and if an effect would not be expected based upon existing data (e.g., from structurally and/or metabolically related compounds), then a full study using three dose levels may not be considered necessary. Expected human exposure may indicate the need for a higher oral dose level to be used in the limit test. For other types of administration, such as inhalation or dermal application, the physico-chemical properties of the test substance often may indicate and limit the maximum attainable level of exposure (for example, dermal application should not cause severe local toxicity).

1.6.5 Administration of doses

The test substance or vehicle is usually administered orally by intubation. If another route of administration is used, the tester should provide justification and reasoning for its selection, and appropriate modifications may be necessary (2)(3)(4). The test substance should be administered at approximately the same time each day.

The dose to individual animals should normally be based on the most recent individual body weight determination. However, caution should be exercised when adjusting the dose during the last trimester of pregnancy. Existing data should be used for dose selection to prevent excess maternal toxicity. However, if excess toxicity is noted in the treated dams, those animals should be humanely killed. If several pregnant animals show signs of excess toxicity, consideration should be given to terminating that dose group. When the substance is administered by gavage, this should preferably be given as a single dose to the animals using a stomach tube or a suitable intubation canula. The maximum volume of liquid that can be administered at one time depends on the size of the test animal. The volume should not exceed 1 ml/100 g body weight, except in the case of aqueous solutions where 2 ml/100 g body weight may be used. When corn oil is used as a vehicle, the volume should not exceed 0.4 ml/100 g body weight. Variability in test volume should be minimised by adjusting the concentrations to ensure a constant volume across all dose levels.

1.6.6 Observations of the dams

Clinical observations should be made and recorded at least once a day, preferably at the same time(s) each day taking into consideration the peak period of anticipated effects after dosing. The condition of the animals should be recorded including mortality, moribundity, pertinent behavioural changes, and all signs of overt toxicity.

1.6.7 Body weight and food consumption

Animals should be weighed on day 0 of gestation or no later than day 3 of gestation if time-mated animals are supplied by an outside breeder, on the first day of dosing, at least every 3 days during the dosing period and on the day of scheduled kill.

Food consumption should be recorded at three-day intervals and should coincide with days of body weight determination.

1.6.8 Post-mortem examination

Females should be killed one day prior to the expected day of delivery. Females showing signs of abortion or premature delivery prior to scheduled kill should be killed and subjected to a thorough macroscopic examination.

At the time of termination or death during the study, the dam should be examined macroscopically for any structural abnormalities or pathological changes. Evaluation of the dams during caesarean section and subsequent foetal analyses should be conducted preferably without knowledge of treatment group in order to minimise bias.

1.6.9 Examination of uterine contents

Immediately after termination or as soon as possible after death, the uteri should be removed and the pregnancy status of the animals ascertained. Uteri that appear non gravid should be further examined (e.g. by ammonium sulphide staining for rodents and Salewski staining or a suitable alternative method for rabbits) to confirm the non-pregnant status (5).

Gravid uteri including the cervix should be weighed. Gravid uterine weights should not be obtained from animals found dead during the study.

The number of corpora lutea should be determined for pregnant animals.

The uterine contents should be examined for numbers of embryonic or foetal deaths and viable foetuses. The degree of resorption should be described in order to estimate the relative time of death of the conceptus (see section 1.2).

1.6.10 Examination of foetuses

The sex and body weight of each foetus should be determined.

Each foetus should be examined for external alterations (6).

Foetuses should be examined for skeletal and soft tissue alterations (e.g. variations and malformations or anomalies) (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Categorisation of foetal alterations is preferable but not required. When categorisation is done, the criteria for defining each category should be clearly stated. Particular attention should be paid to the reproductive tract which should be examined for signs of altered development.

For rodents, approximately one-half of each litter should be prepared and examined for skeletal alterations. The remainder should be prepared and examined for soft tissue alterations, using accepted or appropriate serial sectioning methods or careful gross dissection techniques.

For non-rodents, e.g. rabbits, all foetuses should be examined for both soft tissue and skeletal alterations. The bodies of these foetuses are evaluated by careful dissection for soft tissue alterations, which may include procedures to further evaluate internal cardiac structure (25). The heads of one-half of the foetuses examined in this manner should be removed and processed for evaluation of soft tissue alterations (including eyes, brain, nasal passages and tongue), using standard serial sectioning methods (26) or an equally sensitive method. The bodies of these foetuses and the remaining intact foetuses should be processed and examined for skeletal alterations, utilising the same methods as described for rodents.

2 DATA

2.1TREATMENT OF RESULTS

Data shall be reported individually for the dams as well as for their offspring and summarised in tabular form, showing for each test group and each generation the number of animals at the start of the test, the number of animals found dead during the test or killed for humane reasons, the time of any death or humane kill, the number of pregnant females, the number of animals showing signs of toxicity, a description of the signs of toxicity observed, including time of onset, duration, and severity of any toxic effects, the types of embryo/foetal observations, and all relevant litter data.

Numerical results should be evaluated by an appropriate statistical method using the litter as the unit for data analysis. A generally accepted statistical method should be used; the statistical methods should be selected as part of the design of the study and should be justified. Data from animals that do not survive to the scheduled kill should also be reported. These data may be included in group means where relevant. Relevance of the data obtained from such animals, and therefore inclusion or exclusion from any group mean(s), should be justified and judged on an individual basis.

2.2EVALUATION OF RESULTS

The findings of the Prenatal Developmental Toxicity Study should be evaluated in terms of the observed effects. The evaluation will include the following information:

  • maternal and embryo/foetal test results, including the evaluation of the relationship, or lack thereof, between the exposure of the animals to the test substance and the incidence and severity of all findings;

  • criteria used for categorising foetal external, soft tissue, and skeletal alterations if categorisation has been done;

  • when appropriate, historical control data to enhance interpretation of study results;

  • the numbers used in calculating all percentages or indices;

  • adequate statistical analysis of the study findings, when appropriate, which should include sufficient information on the method of analysis, so that an independent reviewer/statistician can re-evaluate and reconstruct the analysis;

In any study which demonstrates the absence of any toxic effects, further investigations to establish absorption and bioavailability of the test substance should be considered.

2.3INTERPRETATION OF RESULTS

A prenatal developmental toxicity study will provide information on the effects of repeated exposure to a substance during pregnancy on the dams and on the intrauterine development of their progeny. The results of the study should be interpreted in conjunction with the findings from subchronic, reproduction, toxicokinetic and other studies. Since emphasis is placed on both general toxicity in terms of maternal toxicity and on developmental toxicity endpoints, the results of the study will allow to a certain extent for the discrimination between developmental effects occurring in the absence of general toxicity and those which are only induced at levels that are also toxic to the maternal animal (27).

3 REPORTING

TEST REPORT

The test report must include the following specific information:

Test substance:

  • physical nature and, where relevant, physiochemical properties;

  • identification including CAS number if known/established;

  • purity.

Vehicle (if appropriate):

  • justification for choice of vehicle, if other than water.

Test animals:

  • species and strain used;

  • number and age of animals;

  • source, housing conditions, diet, etc.;

  • individual weights of animals at the start of the test.

Test conditions:

  • rationale for dose level selection;

  • details of test substance formulation/diet preparation, achieved concentration, stability and homogeneity of the preparation;

  • details of the administration of the test substance;

  • conversion from diet/drinking water test substance concentration (ppm) to the actual dose (mg/kg body weight/day), if applicable;

  • environmental conditions;

  • details of food and water quality.

Results:

Maternal toxic response data by dose, including but not limited to:

  • the number of animals at the start of the test, the number of animals surviving, the number pregnant, and the number aborting, number of animals delivering early;

  • day of death during the study or whether animals survived to termination;

  • data from animals that do not survive to the scheduled kill should be reported but not included in the inter-group statistical comparisons;

  • day of observation of each abnormal clinical sign and its subsequent course;

  • body weight, body weight change and gravid uterine weight, including, optionally, body weight change corrected for gravid uterine weight;

  • food consumption and, if measured, water consumption;

  • necropsy findings, including uterine weight;

  • NOAEL values for maternal and developmental effects should be reported.

Developmental endpoints by dose for litters with implants, including:

  • number of corpora lutea;

  • number of implantations, number and percent of live and dead foetuses and resorptions;

  • number and percent of pre- and post-implantation losses.

Developmental endpoints by dose for litters with live foetuses, including:

  • number and percent of live offspring;

  • sex ratio;

  • foetal body weight, preferably by sex and with sexes combined;

  • external, soft tissue, and skeletal malformations and other relevant alterations;

  • criteria for categorisation if appropriate;

  • total number and percent of foetuses and litters with any external, soft tissue, or skeletal alteration, as well as the types and incidences of individual anomalies and other relevant alterations.

Discussion of results.

Conclusions.

4 REFERENCES

(1)Kavlock R.J. et al. (1996) A Simulation Study of the Influence of Study Design on the Estimation of Benchmark Doses for Developmental Toxicity. Risk Analysis 16; 399-410.
(2)Kimmel, C.A. and Francis, E.Z. (1990) Proceedings of the Workshop on the Acceptability and Interpretation of Dermal Developmental Toxicity Studies. Fundamental and Applied Toxicology 14; 386-398.
(3)Wong, B.A., et al. (1997) Developing Specialized Inhalation Exposure Systems to Address Toxicological Problems. CIIT Activities 17; 1-8.
(4)US Environmental Protection Agency (1985) Subpart E-Specific Organ/Tissue Toxicity, 40 CFR 798.4350: Inhalation Developmental Toxicity Study.
(5)Salewski, E. (1964) Faerbermethode zum Makroskopischen Nachweis von Implantations Stellen am Uterusder Ratte. Naunyn-Schmeidebergs Archiv fur Pharmakologie und Experimented Pathologie 247:367.
(6)Edwards, J.A. (1968) The external Development of the Rabbit and Rat. Embryo. In Advances in Teratology. D.H.M. Woolam (ed.) Vol. 3. Academic Press, NY.
(7)Inouye, M. (1976) Differential Staining of Cartilage and Bone in Fetal Mouse Skeleton by Alcian Blue and Alizarin Red S. Congenital Anomalies 16; 171-173.
(8)Igarashi, E. et al. (1992) Frequency Of Spontaneous Axial Skeletal Variations Detected by the Double Staining Techniquefor Ossified and Cartilaginous Skeleton in Rat Foetuses. Congenital Anomalies 32;:381-391.
(9)Kimmel, C.A. et al. (1993) Skeletal Development Following Heat Exposure in the Rat. Teratology 47:229-242.
(10)Marr, M.C. et al. (1988) Comparison of Single and Double Staining for Evaluation of Skeletal Development: The Effects of Ethylene Glycol (EG) in CD Rats. Teratology 37; 476.
(11)Barrow, M.V. and Taylor, W.J. (1969) A Rapid Method for Detecting Malformations in Rat Foetuses. Journal of Morphology 127:291-306.
(12)Fritz, H. (1974) Prenatal Ossification in Rabbits ss Indicative of Foetal Maturity. Teratology 11; 313-320.
(13)Gibson, J.P. et al. (1966) Use of the Rabbit in Teratogenicity Studies. Toxicology and Applied Pharmacology 9;:398-408.
(14)Kimmel, C.A. and Wilson, J.G. (1973) Skeletal Deviation in Rats: Malformations or Variations? Teratology 8; 309-316.
(15)Marr, M.C. et al. (1992) Developmental Stages of the CD (Sprague-Dawley) Rat Skeleton after Maternal Exposure to Ethylene Glycol. Teratology 46; 169-181.
(16)Monie, I.W. et al. (1965) Dissection Procedures for Rat Foetuses Permitting Alizarin Red Staining of Skeleton and Histological Study of Viscera. Supplement to Teratology Workshop Manual, pp. 163-173.
(17)Spark, C. and Dawson, A.B. (1928) The Order and Time of appearance of Centers of Ossification in the Fore and Hind Limbs of the Albino Rat, with Special Reference to the Possible Influence of the Sex Factor. American Journal of Anatomy 41; 411-445.
(18)Staples, R.E. and Schnell, V.L. (1964) Refinements in Rapid Clearing Technique in the KOH-Alizarin Red S Method for Fetal Bone. Stain Technology 39; 61-63.
(19)Strong, R.M. (1928) The Order Time and Rate of Ossification of the Albino Rat (Mus Norvegicus Albinus) Skeleton. American Journal of Anatomy 36; 313-355.
(20)Stuckhardt, J.L. and Poppe, S.M. (1984) Fresh Visceral Examination of Rat and Rabbit Foetuses Used in Teratogenicity Testing. Teratogenesis, Carcinogenesis, and Mutagenesis 4; 181-188.
(21)Walker, D.G. and Wirtschafter, Z.T. (1957) The Genesis of the Rat Skeleton. Thomas, Springfield, IL.
(22)Wilson, J.G. (1965) Embryological Considerations in Teratology. In Teratology: Principles and Techniques, Wilson J.G. and Warkany J. (eds). University of Chicago, Chicago, IL, pp 251-277.
(23)Wilson, J.G. and Fraser, F.C. (eds). (1977) Handbook of Teratology, Vol. 4. Plenum, NY.
(24)Varnagy, L. (1980) Use of Recent Fetal Bone Staining Techniques in the Evaluation of Pesticide Teratogenicity. Acta Vet. Acad. Sci: Hung. 28; 233-239.
(25)Staples, R.E. (1974) Detection of visceral Alterations in Mammalian Foetuses. Teratology 9; 37-38.
(26)Van Julsingha, E.B. and C.G. Bennett (1977) A Dissecting Procedure for the Detection of Anomalies in the Rabbit Foetal Head. In: Methods in Prenatal Toxicology Neubert, D., Merker, H.J. and Kwasigroch, T.E. (eds.). University of Chicago, Chicago, IL, pp. 126-144.
(27)US Environmental Protection Agency (1991) Guidelines for Developmental Toxicity Risk Assessment. Federal Register 56; 63798-63826.
(28)Wise, D.L. et al. (1997) Terminology of Developmental Abnormalities in Common Laboratory Mammals (Version 1) Teratology 55; 249-292.

Back to top

Options/Help

Print Options

You have chosen to open the Whole Directive

The Whole Directive you have selected contains over 200 provisions and might take some time to download. You may also experience some issues with your browser, such as an alert box that a script is taking a long time to run.

Would you like to continue?

You have chosen to open Schedules only

The Schedules you have selected contains over 200 provisions and might take some time to download. You may also experience some issues with your browser, such as an alert box that a script is taking a long time to run.

Would you like to continue?

Close

Legislation is available in different versions:

Latest Available (revised):The latest available updated version of the legislation incorporating changes made by subsequent legislation and applied by our editorial team. Changes we have not yet applied to the text, can be found in the ‘Changes to Legislation’ area.

Original (As adopted by EU): The original version of the legislation as it stood when it was first adopted in the EU. No changes have been applied to the text.

Close

Opening Options

Different options to open legislation in order to view more content on screen at once

Close

More Resources

Access essential accompanying documents and information for this legislation item from this tab. Dependent on the legislation item being viewed this may include:

  • the original print PDF of the as adopted version that was used for the EU Official Journal
  • lists of changes made by and/or affecting this legislation item
  • all formats of all associated documents
  • correction slips
  • links to related legislation and further information resources
Close

More Resources

Use this menu to access essential accompanying documents and information for this legislation item. Dependent on the legislation item being viewed this may include:

  • the original print PDF of the as adopted version that was used for the print copy
  • correction slips

Click 'View More' or select 'More Resources' tab for additional information including:

  • lists of changes made by and/or affecting this legislation item
  • confers power and blanket amendment details
  • all formats of all associated documents
  • links to related legislation and further information resources