. 2021 Jul 12;129(7):076002. doi: 10.1289/EHP7381

Table 5.

Summary of studies evaluating reproductive effects.

Author and publication year	Study description	Route of exposure	Exposure measurement	Outcome(s) evaluated^a	Outcomes(s) observed	Overall confidence level for outcome	Applicability for dose–response
Human studies (nonspecific route of exposure)
Singh et al. (2008)	General population case–control study of 60 mothers [31 with full-term deliveries (mean age 25.55 y) and 29 with preterm deliveries (mean age 26.41 y)] in India (Lucknow City).	Nonspecific route of exposure	Placental tissue levels of naphthalene	Preterm birth	Higher placental naphthalene levels among women with preterm vs. full-term birth, but the difference was not statistically significant.	Medium. All domains were evaluated as adequate.	Limited suitability. Study does not adjust for possible confounders. (Information on confounders was collected, but not used directly in the analysis.)
Xia et al. (2009)	General population cross-sectional health survey of 542 men diagnosed with unexplained male factor infertility between 2004 and 2007 (176 controls) in China.	Nonspecific route of exposure	Creatinine-adjusted urinary metabolite levels (1N, 2N)	Sperm parameters (semen volume, sperm concentration, sperm number per ejaculum, and sperm motility)	No association between urinary naphthalene metabolites and below-reference semen parameters	Medium. All domains except sensitivity were evaluated as at least adequate.	Limited suitability. Cross-sectional study design with limited ability to assess temporality. Also, insufficient availability of data or models to relate urinary metabolites to exposure levels.
Yang et al. (2017)	General population cohort study of 933 men from subfertile couples; recruited from an infertility clinic in Wuhan, China in China. Men had no known occupational exposure to PAHs.	Nonspecific route of exposure	Urinary metabolite levels (1N, 2N)	Semen quality (sperm count, sperm concentration, sperm morphology, sperm motility, semen volume)	Significant inverse association between at least one metabolite level and sperm concentration, count, normal morphology, and linearity	Medium. All domains were evaluated as at least adequate.	Limited suitability. Insufficient availability of data or models to relate urinary metabolites to exposure levels.
Yin et al. (2017)	General population cohort study of 109 mother–child pairs (singleton births without congenital problems); recruited between July 2011 and May 2012 at the Shengsi People’s Hospital on the Shengsi Islands (East China Sea) in China.	Nonspecific route of exposure	Umbilical cord serum levels of naphthalene	Reproductive hormone levels in umbilical cord blood serum (testosterone, estradiol, gonadotropins, AMH)	Significant negative association with cord AMH	Medium. All domains except sensitivity were evaluated as at least adequate.	Limited suitability. Hormone measurements at childbirth may not accurately reflect the situation in the infant endocrine system during pregnancy because of negative feedback by placental hormones.
Meeker et al. (2008)	General population cross-sectional health survey of 322 adult males in United States (Massachusetts).	Nonspecific route of exposure	Urinary metabolite levels (1N; 2N also measured but is not shown in the analysis)	Serum reproductive hormone levels: estradiol and prolactin	Nonsignificant inverse association between 1N and estradiol levels	Low. All domains except outcome and exposure measurement were evaluated as adequate. “However, because 1N is a major urinary metabolite of both naphthalene and the insecticide carbaryl, exposure misclassification stemming from differences in exposure source is possible and interpretation of the results is limited.” (Meeker et al. 2007)	Limited suitability. Cross-sectional study design with limited ability to assess temporality. Significant concern for exposure misclassification due to use of urinary 1N. Also, insufficient availability of data or models to relate urinary metabolites to exposure levels.
Meeker et al. (2006)^a	General population cross-sectional health survey of 322 adult males (mean age 36.1 y) in United States (Massachusetts).	Nonspecific route of exposure	Urinary metabolite levels (1N)	Serum reproductive hormone levels: gonadotropins, inhibin B, testosterone, and sex hormone-binding globulin	Inverse association with testosterone	Low. All domains except outcome and exposure measurement were evaluated as adequate. “However, because 1N is a major urinary metabolite of both naphthalene and the insecticide carbaryl, exposure misclassification stemming from differences in exposure source is possible and interpretation of the results is limited.” (Meeker et al. 2007)	Limited suitability. Cross-sectional study design with limited ability to assess temporality. Significant concern for exposure misclassification due to use of urinary 1N. Also, insufficient availability of data or models to relate urinary metabolites to exposure levels.
Meeker et al. (2004a)^a	General population cross-sectional health survey of 272 adult men in United States (Massachusetts).	Nonspecific route of exposure	Urinary metabolite levels (1N)	Sperm parameters	Statistically significant association with below-reference sperm concentration and percent motile sperm; nonsignificant association with abnormal sperm morphology	Low. All domains except exposure measurement were evaluated as at least adequate. “However, because 1N is a major urinary metabolite of both naphthalene and the insecticide carbaryl, exposure misclassification stemming from differences in exposure source is possible and interpretation of the results is limited.” (Meeker et al. 2007)	Limited suitability. Cross-sectional study design with limited ability to assess temporality. Significant concern for exposure misclassification due to use of urinary 1N. Also, insufficient availability of data or models to relate urinary metabolites to exposure levels.
Meeker et al. (2004b)^a	General population cross-sectional health survey of 260 adult men (mean age 36.1 y) in United States (Massachusetts).	Nonspecific route of exposure	Urinary metabolite levels (1N)	DNA damage in sperm, measured using comet assay	Association with DNA damage in sperm (statistically significant for % DNA located in comet tail; not significant for comet extent and tail distributed moment)	Low. All domains except exposure measurement were evaluated as at least adequate. “However, because 1N is a major urinary metabolite of both naphthalene and the insecticide carbaryl, exposure misclassification stemming from differences in exposure source is possible and interpretation of the results is limited.” (Meeker et al. 2007)	Limited suitability. Cross-sectional study design with limited ability to assess temporality. Significant concern for exposure misclassification due to use of urinary 1N. Also, insufficient availability of data or models to relate urinary metabolites to exposure levels.
Animal studies (inhalation)
Dodd et al. (2012)	Male and female rats (Fischer 344); 90-d exposure	Inhalation (whole body)	0, 0.5, 5.2, 52, $157 {mg / m}^{3}$	Testis, ovary, and uterus weight	Statistically significant decrease in absolute testis weight	High. This study was well-designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable for testis data only. Multidose study; quantitative data reported for testis but not ovary or uterus.
NTP (2000)	Male and female rats (Fischer 344); 2-y (105-wk) exposure	Inhalation (whole body)	0, 52, 157, $314 {mg / m}^{3}$	Histopathology of testis, epididymis, seminal vesicles, preputial gland, prostate, ovary, uterus, clitoral gland, and mammary glands	No effects observed	High. This study was well-designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.
NTP (1992b)	Male and female mice (B6C3F1); 2-y (103-wk) exposure	Inhalation (whole body)	0, 52, $157 {mg / m}^{3}$	Histopathology of testis, epididymis, seminal vesicles, prostate, ovaries, uterus, and mammary glands	No effects observed	High (females). This study was well designed to evaluate these outcomes. Evidence was presented clearly and transparently. Low (males). The high mortality rate in control males has the potential to interfere with the interpretation of results.	Suitable. Multidose study with quantitative data.
Animal studies (oral)
Battelle (1980b)	Male and female rats (Fischer 344); 90-d exposure	Oral gavage	0, 25, 50, 100, 200, $400 mg / kg-d$	Histopathology of testis, prostate, ovaries, uterus, and mammary glands	No effects observed	High. This study was well-designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.
Battelle (1980a)	Male and female mice (B6C3F1); 90-d exposure	Oral gavage	0, 12.5, 25, 50, 100, $200 mg / kg-d$	Histopathology of testes, prostate, ovaries, uterus, and mammary glands	No effects observed	High. This study was well-designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.
NTP (1992a)^b	Female rabbits (New Zealand); exposure from GD 6–19, sacrifice on GD 30	Oral gavage	0, 20, 80, $120 mg / kg-d$	Maternal body weight gain, gravid uterine weight, number pregnant at sacrifice	Decreased maternal body weight gain during treatment period (statistically significant trend)	Low (maternal body weight, uterine weight). Rabbit maternal body weight gain is known to have high variability, and therefore this is not an ideal species to use for evaluating this end point. High (number pregnant at sacrifice). This study was well-designed to evaluate this outcome. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.
NTP (1991)^b	Female rats (Sprague-Dawley); exposure from GD 6–15, sacrifice on GD 20	Oral gavage	0, 50, 150, $450 mg / kg-d$	Maternal body weight gain, gravid uterine weight, number pregnant at sacrifice	Statistically significant decrease in maternal body weight gain during gestation (corrected for gravid uterine weight)	High. This study was well-designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.
Pharmakon Research (1985)^b^,^c	Female rabbits (New Zealand); exposure from GD 6–18, sacrifice on GD 29	Oral gavage	0, 50, 250, 630, $1,000 mg / kg-d$	Maternal body weight gain, uterine weight, number pregnant at sacrifice	Statistically significant decrease in maternal body weight during gestation (occurring at doses with high maternal mortality)	Low (maternal body weight, uterine weight). Rabbit maternal body weight gain is known to have high variability, and therefore this is not an ideal species to use for evaluating this end point. High (pregnant at sacrifice). This study was well-designed to evaluate this outcome. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.
Shopp et al. (1984)	Male and female mice (CD-1); 14- or 90-d exposure	Oral gavage	14-d exposure: 0, 27, 53, $267 mg / kg-d$ 90-d exposure: 0, 5.3, 53, $133 mg / kg-d$	Testis weight	No effects observed	High. This study was well-designed to evaluate this outcome. Evidence was presented clearly and transparently.	Suitable. Multidose studies with quantitative data.
Plasterer et al. (1985)	Female mice (CD-1); exposure from GD 7–14, dams allowed to deliver	Oral gavage	0, $300 mg / kg-d$	Maternal body weight gain, reproductive index (survivors delivered/pregnant survivors)	Statistically significant decrease in maternal body weight gain during gestation	Medium (maternal body weight). Body weight gain was not able to be corrected for gravid uterine weight (due to the dams giving live birth), which affects the usability of the data because maternal toxicity cannot be distinguished from fetal toxicity. High (reproductive index). This study was well-designed to evaluate this outcome. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.
Pharmakon Research (1986)^b	Female rabbits (New Zealand); exposure from GD 6–18, sacrifice on GD 29	Oral gavage	0, 40, 200, $400 mg / kg-d$	Maternal body weight gain, premature delivery, number pregnant at sacrifice	No effects observed	Low (maternal body weight). Rabbit maternal body weight gain is known to have high variability, and therefore this is not an ideal species to use for evaluating this end point. High (premature delivery, pregnant at sacrifice). This study was well-designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.
Animal studies (dermal)
Bushy Run (1986)	Male and female rats (Sprague-Dawley CD); 90-d exposure	Dermal	0, 100, 300, $1,000 mg / kg-d$	Gonad weights; histopathology of testes, epididymis, seminal vesicles, prostate, vagina, ovaries, uterus, and mammary glands.	Statistically significant decrease in absolute and relative testes weight (no effects on testis weight observed in subgroup allowed to recover for 4 wk after exposure)	High. This study was well designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.

Note: AMH, anti-Müllerian hormone; GD, gestational day; HAWC, U.S. EPA Health Assessment Workspace Collaborative; PAH, polycyclic aromatic hydrocarbons: .

^{^a}

Meeker et al. (2007) presents a reanalysis of data from Meeker et al. 2004a, 2004b, and 2006; not shown in this table.

^{^b}

Corpora lutea counts from gestational exposure studies would not have been affected by naphthalene exposure because all exposures began after animals were already pregnant. Corpora lutea counts from these studies may be useful as a metric of baseline fertility and are extracted in HAWC but are not discussed in this table.

^{^c}

Pharmakon Research (1985) was a dose-range finding study with a 50% maternal mortality rate at $630 mg / kg - d$ and 100% mortality at $1,000 mg / kg - d$ .