Intent to Change the Basis for Listing as Known to the State of California to Cause Reproductive Toxicity: Nitrous Oxide

The California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) intends to change the basis for the listing of nitrous oxide as known to the state to cause reproductive toxicity under the Safe Drinking Water and Toxic Enforcement Act of 1986[1].  

Nitrous oxide was originally added to the Proposition 65 list as causing reproductive toxicity on August 1, 2008 pursuant to Labor Code Section 6382(d), which is incorporated by reference in Health and Safety Code Section 25249.8(a).  Nitrous oxide was listed based on its identification as causing developmental toxicity in the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values (TLVs). The TLVs were previously incorporated by reference into the federal Occupational Health and Safety Administration (OSHA) Hazard Communication Standards (Title 29, Code of Federal Regulations, section 1900.1200) [2].

OEHHA is initiating this action based on changes to certain federal regulations that affect the basis for the original listing.  Specifically, in March 2012, OSHA extensively amended the regulations contained in Title 29, C.F.R., section 1910.1200.  Title 29, C.F.R 1910.1200(d)(3)(ii), which specifically referred to the ACGIH TLV list, was deleted in the 2012 version of the regulation.  OEHHA has determined that these changes have eliminated the ACGIH TLVs as a definitive source for identifying chemicals that are known to cause reproductive toxicity. 

However, OEHHA has determined that nitrous oxide meets the criteria for listing via the “authoritative bodies” listing mechanism[3] and is providing this notice of its intent to change the basis for listing the chemical based on developmental and female reproductive toxicity.  Nitrous oxide will not be removed from the Proposition 65 list during this process.

Background on listing via the authoritative bodies mechanism: A chemical must be listed under Proposition 65 and its implementing regulations (Section 26306) when two conditions are met:

1. An authoritative body formally identifies the chemical as causing reproductive toxicity (Section 25306(d)(1).
2. The evidence considered by the authoritative body meets the sufficiency criteria contained in the regulations (Section 25306(g)). 

However, the chemical is not listed if scientifically valid data that were not considered by the authoritative body clearly establish that the sufficiency of evidence criteria were not met (Section 25306(h)). 

The National Institute for Occupational Safety and Health (NIOSH) is one of several institutions designated as an authoritative body for the identification of chemicals as causing reproductive toxicity (Section 25306(l)).

OEHHA is the lead agency for implementation of Proposition 65[4].  After an authoritative body has made a determination that a chemical causes cancer or reproductive toxicity, OEHHA evaluates whether listing under Proposition 65 is required using the criteria contained in the regulations.

OEHHA’s determination: Nitrous oxide (N₂O) meets the criteria for listing as known to the State to cause reproductive toxicity under Proposition 65, based on findings of NIOSH (NIOSH, 1994a,b), as outlined below.

Formal identification and sufficiency of evidence: OEHHA is relying on NIOSH’s conclusion that N₂O causes developmental and female reproductive effects.  This conclusion meets the formal identification requirement of Section 26306(d)(1)[5] and is made in two NIOSH documents:

• ALERT: (Request for Assistance in) Controlling Exposures to Nitrous Oxide During Anesthetic Administration (NIOSH, 1994a)
• Technical Report: Control of Nitrous Oxide in Dental Operatories (NIOSH, 1994b)

NIOSH cites both animal and human studies in support of its identification of N₂O as causing developmental and female reproductive toxicity (NIOSH, 1994a,b). 

The conclusions in the NIOSH reports include the following:

• “CONCLUSIONS...Data from animal studies demonstrate that exposure to N₂O may cause adverse reproductive effects. Studies of workers exposed to N₂O have reported adverse health effects such as reduced fertility, spontaneous abortion, and neurological, renal, and liver disease. The recommendations in this Alert should therefore be followed to minimize worker exposures.” (page 3, NIOSH, 1994a)
• “HEALTH EFFECTS.  Animal studies have shown adverse reproductive effects in female rats exposed to airborne concentrations of N₂O [Corbett et al.1973; Vieira 1979; Vieira et al. 1980, 1983]. Data from these studies indicate that exposure to N₂O during gestation can produce adverse health effects in the offspring.” (page 2, NIOSH, 1994a)
• “Several studies of workers have shown that occupational exposure to N₂O causes adverse effects such as reduced fertility [Rowland et al. 1992], spontaneous abortions, and neurologic, renal, and liver disease [Cohen et al. 1980]. A recent study [Rowland et al. 1992] reported that female dental assistants exposed to unscavenged N₂O for 5 or more hours per week had a significant risk of reduced fertility compared with unexposed female dental assistants. The exposed assistants had a 59% decrease in probability of conception for any given menstrual cycle compared with the unexposed assistants. For dental assistants who used scavenging systems during N₂O administration, the probability of conception was not significantly different from that of the unexposed assistants.” (page 2, NIOSH, 1994a)
•   “Be aware that N₂O may cause the following health effects:
  • Decreases in mental performance, audiovisual ability, and manual dexterity
  • Adverse reproductive effects” (worker factsheet included in NIOSH, 1994a)

In addition, NIOSH has otherwise identified nitrous oxide as causing reproductive toxicity by basing a Recommended Exposure Limit in part on that toxicological endpoint.[6]

“The NIOSH Recommended Exposure Limit (REL) is 25 parts per million (ppm) of air or less during administration.  The REL is based on avoidance of reproductive and impaired psychomotor health effects.” (page iii, NIOSH, 1994b)

The cited reports (NIOSH, 1994a,b) meet the formal identification criterion in Section 25306(d)(2)(C)[7].

OEHHA has reviewed the studies or study descriptions cited by NIOSH (1994a,b) as providing the basis for NIOSH’s conclusions regarding the female reproductive and developmental toxicity of N₂O, relative to the criteria in Section 25306(g).  The criteria for listing N₂O as known to cause reproductive toxicity by the authoritative bodies mechanism have been met.  Therefore, OEHHA has determined that N₂O must stay on the Proposition 65 list, and an additional endpoint should be added to the existing listing.

Request for comments:  OEHHA is requesting comments as to whether this chemical meets the criteria set forth in the Proposition 65 regulations for listings via the authoritative bodies mechanism (Section 25306) and should, therefore, remain on the list of chemicals known to the state to cause reproductive toxicity, with the additional endpoint of female reproductive toxicity. 

In order to be considered, comments must be received by OEHHA by 5:00 p.m. on MONDAY October 21, 2013.  We encourage you to submit comments in electronic form, rather than in paper form.  Comments transmitted by e-mail should be addressed to P65Public.comments@oehha.ca.gov.  Please include “nitrous oxide” in the subject line. Comments submitted in paper form may be mailed, faxed, or delivered in person to the address below.

Mailing Address: Office of Environmental Health Hazard Assessment
P.O. Box 4010, MS-19B
Sacramento, California 95812-4010

Fax: (916) 323-2265

Street Address: 1001 I Street
Sacramento, California 95814

Comments received during the public comment period will be posted on the OEHHA web site after the close of the comment period. 

If you have any questions, please contact the Proposition 65 Office at P65Public.Comments@oehha.ca.gov or at (916) 445-6900.

Comment Period

• Comment Period - Intent to Change the Basis for Listing as Known to the State of California to Cause Reproductive Toxicity: Nitrous Oxide

Chemical Reference

• Nitrous Oxide

Related Notices

• Notice of Change in the Basis for Listing as Known to the State of California to Cause Reproductive Toxicity: Nitrous Oxide and Dichloroacetic Acid

  Nov 8, 2013
• Chemicals Listed Effective August 1, 2008 as Known to the State of California to Cause Cancer or Reproductive Toxicity: gallium arsenide, hexafluoroacetone, nitrous oxide and vinyl cyclohexene dioxide

  Aug 1, 2008
• Request for Comments on Proposed Listing of Gallium Arsenide as Known to Cause Cancer and Hexafluoroacetone, Nitrous Oxide and Vinyl Cyclohexene Dioxide as Known to Cause Reproductive Toxicity

  Jun 15, 2007

Footnotes and References

National Institute for Occupational Safety and Health (NIOSH), 1994a. NIOSH Alert: Request for Assistance in] Controlling Exposures to Nitrous Oxide During Anesthetic Administration.  NIOSH Publication No. 94-100. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention , NIOSH, April 1994. Available online at: http://www.cdc.gov/niosh/docs/94-100/.

National Institute for Occupational Safety and Health (NIOSH), 1994b. Technical Report: Control of Nitrous Oxide in Dental Operatories. NIOSH Publication No. 94-129.  U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, NIOSH, Division of Physical Sciences and Engineering, Engineering Control Technology Branch, Cincinnati, OH.  September 1994.  (Authors: McGlothlin James D., Crouch Keith G., Mickelson R. L.) Available online at : http://www.cdc.gov/niosh/docs/94-129/pdfs/94-129.pdf.

[7] “[the document is] Published by the authoritative body in a publication such as, but not limited to, the federal register…”