Hazard-specific Issues - Substances Assessed For Reproductive and Developmental Hazards

• Reproductive health hazards - overview
• WHMIS classification and hazard communication
• WHMIS in the workplace
• Pregnant / nursing workers
• Designations-explanatory notes
• Substances assessed for reproductive hazards
• Substances assessed for developmental hazards
• References / Related Sites

Disclaimer

Information contained in this section is of a general nature only and is not intended to constitute advice for any specific fact situation.

Reproductive Health Hazards - Overview:

Reproductive health hazards are typically defined as chemical, physical, or biological agents that can cause either reproductive impairment or adverse developmental effects. Developmental toxicity can include fetal death, structural abnormalities or birth defects, and functional deficiencies or altered growth.

The United States Environmental Protection Agency has defined reproductive toxicity as the "occurrence of adverse effects on the reproductive system that may result from exposure to environmental agents. Toxicity may be expressed as alterations to the reproductive organs and/or the related endocrine system" and developmental toxicity as the "occurrence of adverse effects on the developing organism that may result from exposure before conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism."

Under the the Globally Harmonized System (GHS), reproductive toxicity is subdivided under two main headings, "Adverse effects on reproductive ability or capacity" and "Adverse effects on development of the offspring." Under the GHS (United Nation, 2003), adverse effects on reproductive ability or capacity, refer to "any effect of chemicals that would interfere with reproductive ability or capacity. This may include, but not be limited to, alterations to the female and male reproductive system, adverse effects on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour, fertility, parturition, premature reproductive senescence, or modifications in other functions that are dependent on the integrity of the reproductive systems. Adverse effects on or via lactation are also included in reproductive toxicity, but for classification purposes, such effects are treated separately."

Under the GHS (United Nations, 2003), developmental toxicity "includes any effect which interferes with normal development of the conceptus, either before or after birth, and resulting from exposure of either parent prior to conception, or exposure of the developing offspring during prenatal development, or postnatally, to the time of sexual maturation. .... Therefore, for pragmatic purposes of classification, developmental toxicity essentially means adverse effects induced during pregnancy, or as a result of parental exposure. These effects can be manifested at any point in the life span of the organism. The major manifestations of developmental toxicity include (a) death of the developing organism, (b) structural abnormality, (c) altered growth, and (d) functional deficiency."

In the workplace adverse effects have been known for many years. For example, more than 100 years ago, lead was found to cause miscarriages, stillbirths, and infertility in female pottery workers. Biohazardous agents can also have advers effects. Rubella (German measles) was recognized as a major cause of birth defects in the 1940s. However, the causes of most reproductive health problems are still not known for certainty as there may be confounding factors.

WHMIS Classification and Hazard Communication:

The [WHMIS] Controlled Products Regulations (CPR) set out specific criteria for teratogenicity and embryotoxicity and for reproductive toxicity under section 53 and 55, respectively. Subparagraph 33(3)(b)(v) allows for the use of

"any other test or method that is carried out in accordance with generally accepted standards of good scientific practice at the time the test is carried out"

Developmental Toxicity - As per section 53 of the CPR

53. (1) "A pure substance or tested mixture falls into Subdivision A of Division 2 of Class D - Poisonous and Infectious Material if, in an animal assay for teratogenicity and embryotoxicity, it is shown to cause injury to the embryo or fetus in a statistically significant proportion of the test population at a concentration that has no adverse effect on the pregnant female when tested in accordance with

• (a) OECD Test Guideline No. 414, "Teratogenicity", dated May 12, 1981;
• (b) OECD Test Guideline No. 415, "One-Generation Reproduction Toxicity", dated May 26, 1983; or
• (c) OECD Test Guideline No. 416, "Two-Generation Reproduction Toxicity", dated May 26, 1983.

(2) In this section, "injury" includes death, malformation, permanent metabolic or physiological disfunction, growth retardation or psychological or behavioural alteration that occurs during pregnancy, at birth or in the postnatal period."

Additionaly, subparagraph 33(3)(b)(iii) of the CPR references

"in the case of a test for teratogenicity, a test or method described in Principles for the Testing of Drugs for Teratogenicity, Technical Report Series Number 364, published in 1967 by the World Health Organization"

For the purposes of subsection 53(1), the following indicators of maternal toxicity shall be evaluated when determining whether embryo-fetal or developmental toxicity has occurred at "a concentration that has no adverse effect on the pregnant female" (please see the Reference Manual for additional information):

1. Mortality
2. Maternal Body Weight
3. Maternal Body Weight Change
4. Organ Weights
5. Food and Water Consumption
6. Clinical Observations of Toxicity
   
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Reproductive Toxicity - As per section 55 of the CPR

55. A pure substance or tested mixture falls into Subdivision A of Division 2 of Class D - Poisonous and Infectious Material if

• (a) there is evidence that shows that it causes sterility or an adverse effect on reproductive capability in persons following exposure to it in the work place; or
• (b) sterility or an adverse effect on reproductive capability is shown in an animal assay for reproductive toxicity carried out in accordance with
  • (i) OECD Test Guideline No. 415, "One-Generation Reproduction Toxicity", dated May 26, 1983, or
  • (ii) OECD Test Guideline No. 416, "Two-Generation Reproduction Toxicity", dated May 26, 1983."

In contrast to the CPR criteria set out in section 53 for teratogenicity and embryotoxicity, there are no analogous criteria specified for systemic toxicity in relation to the CPR criteria for reproductive toxicity. However, in relation to CPR Schedule I Subitem 7(8) - "Reproductive toxicity", and Subitem 7(9) - "Teratogenicity", the Intergovernmental WHMIS Coordinating Committee's "Guidelines for the Disclosure of Toxicological Information on a Material Safety Data Sheet" states:

"In animal bioassays, adverse effects on fetal development or parental reproductive functions may occur at doses above or below those producing signs of toxicity in the parent animals. The handling, storage or use of controlled products may occasionally produce exposures resulting in mild parental toxicity thereby resulting in potential developmental or reproductive toxicity hazards. For the purpose of MSDS disclosure, any indication of an adverse effect on fetal development or reproductive parameters must be disclosed on the MSDS irrespective of whether or not there is an adverse effect on the pregnant female. Any relevant epidemiological evidence must also be disclosed."

Therefore, as per the Guidelines, toxicity in the parent animals would address both endpoints. However, since there is no reference to systemic toxicity in Section 55 of the CPR, a chemical could be classified as a reproductive toxin in the presence of systemic toxicity. Professional judgement will be required to assess whether the data are adequate and to determine the extent or impact systemic toxicity has on reproductive parameters.

Regarding hazard communication, the "Guidelines for the Disclosure of Toxicological Information on MSDSs" (WHMIS, 1997) state that:

"For the purpose of hazard disclosure, any indication of an adverse effect on fetal development or reproductive parameters should be disclosed on the MSDS. Such disclosure is required because the handling, storage or use of controlled products may occasionally produce exposures resulting in mild parental toxicity, thereby resulting in potential developmental or reproductive toxicity hazards."

WHMIS In The Workplace:

In 1986, Motherisk, a program at Toronto's Hospital for Sick Children, began a prospective study to provide information on the teratological impact of solvents on working mothers. Between 1986 and 1996 the pregnancies of women who had visited the clinic with concerns about solvent exposure on the job were tracked.

The study results were published bu Khattan et al. (1999) in the Journal of the American Medical Association in. Of the 125 women of the exposed group, 13 had given birth to babies that exhibited major malformations such as heart and spine defects, congenital deafness, clubfoot, spina bifida and other neural tube defects. There was one major malformation amongst the babies of the control group. In addition, in the babies of the exposed versus the controlled group, the incidence of minor malformations was 5 to 1, neonatal eczema 12 to 2 and premature births 9 to 3. Whatever limitations the study may have had, the results are epidemiologically significant and demonstrate the need for pregnant workers and both female and male workers planning to have children to adhere to the health and safety information communicated on WHMIS labels and MSDSs.

Pregnant / Nursing Workers:

Provincial and territorial occupational health and safety legislation may have provisions analogous to that afforded pregnant and/or nursing workers in federally regulated workplaces under the Canada Labour Code. Explicit provisions are provided under section 132(1) of Part II of the Code:

132. (1) In addition to the rights conferred by section 128 and subject to this section, an employee who is pregnant or nursing may cease to perform her job if she believes that, by reason of the pregnancy or nursing, continuing any of her current job functions may pose a risk to her health or to that of the foetus or child. On being informed of the cessation, the employer, with the consent of the employee, shall notify the work place committee or the health and safety representative.

This provision relates to a perceived health risk to the foetus or child. It may be exercised from the beginning of the pregnancy until the employee is no longer breast feeding and ensures that employees are paid during the period needed to obtain a medical opinion respecting the perceived risk. This provision is not part of the refusal process, but a separate right; one that gives an employee the opportunity to remove herself from a possible hazard until a medical certificate is obtained. The certificate would then allow her further protection under Section 204 (Part III) of the Code, a collective agreement or any terms and conditions of employment (Treasury Board Maternity-Related Reassignment or Leave Policy). As the terms and conditions of employment applicable to Public Service employees meet or exceed the protection provided by Part III of the Code, there should be minimal impact in the Public Service.

Designations - Explanatory Notes:

California Environmental Protection Agency

• Yes
  Substances "Known to the State to cause reproductive toxicity" included on list of reproductive hazards (Proposition 65 list)
• Male and / or Female
  Substances known to the state to cause reproductive toxicity in the male, female or in both.

European Union

Category 1		Category 2		Category 3
Human evidence Positive epidemiology data on either fertility or developmental hazard		Animal evidence Clear evidence of a specific effect on either fertility or developmental hazard		Animal evidence Less convincing evidence or where doubts about relevance
Fertility	Developmental Toxicity	Fertility	Developmental Toxicity	Fertility	Developmental Toxicity
T; R60	T; R61	T; R60	T; R61	T; R62	T; R63

Notations:

• T - Toxic
• Xn - Harmful
• R60 - May impair fertility
• R61 - May cause harm to the unborn child
• R62 - Possible risk of impaired fertility
• R63 - Possible risk of harm to the unborn child

Substances Assessed For Reproductive Hazards:

The following are two lists that consist of substances assessed for reproductive toxicity. They are compiled based on data from the California EPA list of "chemicals known to the state to cause reproductive toxicity" (January 25, 2002) and on the list of substances classified in the EU as toxic to reproduction (OECD, 1999).

• Substances Assessed for Reproductive Toxicity

Substances Assessed For Developmental Hazards:

The following are two lists that consist of substances assessed for developmental toxicty. They are compiled based on data from the California EPA list of "chemicals known to the state to be toxic to reproduction" (January 25, 2002) and on the list of substances classified in the EU as toxic to reproduction (OECD, 1999).

• Substances Assessed for Developmental Hazards

References / Relates Sites:

• Khattak, S., K-Moghtader, G., McMartin, K., Berra, M., Kennedy, D., Koren, G., 1999. Pregnancy outcome following gestational exposure to organic solvents: A prospective controlled study. JAMA. 281 : 1106-1109.
• US Environmental Protection Agency. Proposed Guidelines for assessing female reproductive risk. Fed Reg. 1988; 53:24834-24847.
• US Environmental Protection Agency. Guidelines for developmental toxicity risk assessment. Fed Reg. 1991; 56:63798-63826.
• OECD- "Detailed Review Document on Classification Systems for Reproductive Toxicity in OECD Member Countries" OECD Series 15, 1999.
• United Nations. 2003.Globally Harmonized System of Classification and Labelling of Chemicals (GHS) "Pupule Book". New york and Geneva.
• Workplace Hazardous Material Information System (WHMIS), 1997. Guidelines for the Disclosure of Toxicological Information on MSDSs.