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Description of key information

- Hazleton UK (1989): 28 day feeding study in SD rats (0, 25, 100, 400 mg/kg bw/day); CAS 84852-15-3; equivalent to OECD 407; LOAEL = 400 mg/kg bw/day; NOAEL = 100 mg/kg/day

- Cunny (1997): 90 day feeding study in SD rats (0, 15, 50, 150 mg/kg bw/day); CAS 84852-15-3; according U.S. EPA TSCA guideline; LOAEL = 150 mg/kg/d; NOAEL = 50 mg/kg/d

- Hard (1998): Pathology report on histopathological findings from the 90 day feeding study conducted by Cunny et al. 1997

- Woo (2007): 28 day gavage study in SD rats (0, 10, 50, 250 mg/kg bw/d); CAS 84852-15-3; No details on isomer composition/purity; GLP; similar to OECD 407; LOAEL = 50 mg/kg bw/d; NOAEL =10 mg/kg bw/d;

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
15 mg/kg bw/day
Study duration:

Additional information

Repeated dose toxicity was assessed in oral sub acute and sub chronic studies (28/90 days) using different routes of administration (diet/gavage). Data were complemented by results from multi-generation studies [referenced in IUCLID 7.8.1].

In a 28 day feeding study in SD rats Nonylphenol (98%) was administered to 5 SD rats/sex/dose at dose levels of 0, 25, 100, 400 mg/kg/d (Hazleton UK, 1989). No mortalities or treatment related clinical signs of toxicity were observed. At 400 mg/kg/d, body weight gain, food consumption and food utilization was significantly reduced throughout the study for both sexes. There were slight deviations in certain clinical chemistry parameters in males (urea and cholesterol levels were increased; glucose levels were reduced). Group mean relative kidney, liver and testes weights were increased (all by about 20% compared with controls). Histopathological examination revealed hyaline droplet accumulation in the renal proximal tubules (an effect considered to be of no relevance to human health) and a minor vacuolation in periportal hepatocytes in males. Among the females at this level, there were no treatment-related changes in the organs. 400 mg/kg/d are considered to be the LOAEL. NOAEL is 100 mg/kg/d. This NOAEL is based on expert judgement in accordance with EU RAR 2002. The study report states “a no effect level for males was not found”. This conclusion is based on minor increases of kidney, adrenal and liver weights and for the incidence of minimal hyaline droplet formation in the kidney of males at 25 and 100 mg/kg/d. All minor effects were within the laboratory's historical control range and confirmatory changes were not seen for adrenal and liver weight or hyaline droplet formation in a 90-day study (Cunny 1997).

In a 90 day feeding study in SD rats Nonylphenol [CAS 84852-15-3] (95.6%) was administered to 15 SD rats/sex/dose at dose levels of 0, 15, 50, 150 mg/kg/d (Cunny 1997). A NOAEL of 50 mg/kg/d was concluded. No treatment-related effects on endocrine organs, estrous cycling, or sperm measurements were seen at any dose. The LOAEL is 150 mg/kg/d based on a small decrease in body weight gain, food consumption, food utilization, together with evidence of morphological changes in the liver and possibly kidneys. Morphological changes in the liver were found in females in the high dose group. Three animals showed slight or moderate individual hepatic cell necrosis. Two of the affected females also had raised serum aspartate aminotransferase (ALT) and alanine aminotransferase (AST). This provides evidence that the liver may be a target organ for nonylphenol toxicity, although this evidence is weak in view of the mild nature of response and small number of animals affected.

A dose-related increase of kidney weight and a decrease in renal hyaline globules/droplets were observed in males. This effect on kidney weight showed complete recovery following the 4-week post dosing recovery period. Due to the small magnitude of the changes (i.e., all weights were within or near laboratory historical control values) and the lack of correlating clinical or histopathological changes, the kidney weight alterations were not considered toxicologically significant. The biological significance of reduced hyaline in the kidneys is uncertain. Renal tubular hyaline is associated with the rat-specific protein, a-2u-globulin, and, therefore, this finding was not considered toxicologically relevant to humans. Also, a lack of correlation with the findings of the 28- day repeated dose study (Hazleton UK (1989)), in which an actual increase in the incidence of renal hyaline droplets occurred, casts doubt on whether these changes should be considered to be related to treatment. The renal histopathological findings were reviewed by a pathologist (Hard 1998). The predominant renal lesions were described as tubular mineralisation at the OSOM/ISOM junction, cystic tubules surrounded by fibrosis, or granular cast formation at the OSOM/ISOM junction. 11 out of 25 from the high dose group were affected, compared with 1 out of 25 control males. Hence, there is evidence of morphological changes in the kidneys.


In addition to the feeding studies there are two repeated dose toxicity studies administering Nonylphenol by gavage. In a 28 day study in SD rats Nonylphenol [CAS 84852-15-3] (95.6%) was administered to 10 animals/sex/dose at dose levels of 0, 10, 50, 250 mg/kg/d (Woo, 2007). A NOAEL of 10 mg/kg/d was concluded. The LOAEL of 50 mg/kg/d based on some small but significant alteration of glucose and inorganic phosphates levels in females; increase of thyroid weight in males and increase of serum LH in female. At 250 mg/kg/d mortality and clinical signs occur. Three females died or became moribund during the experiment. Hepatic and renal toxicity was evident in both sexes with increase of relative liver and kidney weights as well as histopathological changes, such as centrilobular liver cell hypertrophy and a variety of renal tubular lesions, and alteration of serum biochemical parameters.

Another gavage study was conducted by de Jager (1999) to investigate testicular toxicity in rats. In this study, mortality was observed at 100 (the lowest dose level tested), 250 and 400 mg/kg/d; 3, 15 and 18 out of 20 animals in each group died during a 10-week dosing period. No further information on these mortalities is available. The presence of mortality at such dose levels contrasts with the findings of the dietary administration studies (Hazleton, 1989 (28 days); Cunny, 1997 (90 days); Chapin, 1999 (multi-generation)). The differences can probably be accounted for by the method of administration; gavage dosing is likely to produce higher peak concentrations of nonylphenol in the blood than dietary administration. This can be explained by toxicokinetic data. Higher peak concentration saturate the metabolic capacity of the liver and GI tract first pass effect resulting in a decreased detoxification and consequently a higher internal dose.


Additional information on repeated dose toxicity can be derived from multi-generation studies. An EPA OPPTS 870.3800 guideline study (Chapin 1999; NTP 1997) was assessed in the EU Risk Assessment Report (EU RAR) 2002. In this 3.5 generation feeding study 0, 200, 650, and 2000 ppm (~0, 15, 50, 160 mg/kg/d) Nonylphenol [CAS 84852-15-3] was administered to 30 SD rats/sex/dose. At 150 mg/kg/d, bodyweight gain was reduced in comparison with controls in adults across all generations. Similar reductions in body weight gain were seen at 50 mg/kg/d in F1 females, F2 males and F3 females. Relative kidney weights were increased at 50 and/or 160 mg/kg/d in adult males of the F0, F1 and F2 generations and also at 160 mg/kg/d in F1 adult females. Histopathological examination revealed an increase, although often without a convincing dose-response relationship, in the incidence of renal tubular degeneration and/or dilatation in adult males from all generations and all nonylphenol treated groups; similar findings were reported for adult females at 160 mg/kg/d in the F1, F2 and F3 generations and at 15 and 50 mg/kg/d in the F3 generation. The increased incidence of renal tubular degeneration and/or dilatation was not seen to the same extent in the 90-day study (Cunny, 1997), which was conducted using the same strain of rats. In addition a dose-dependent trend was not apparent in all generations/sexes. The lack of concordance between the studies cannot be explained on the basis of a slightly longer exposure period in the multi-generation study because kidney effects were seen in the F3 generation which was exposed for only 8 weeks, nor on the basis of in utero and neonatal exposure because the effect also occurred in the F0 generation. Giving special emphasis to the fact that the increased incidence occurred consistently across all four generations in the multi-generation study, it is considered that this cannot be dismissed as background variation. The EU risk assessment 2002 concluded a LOAEL for repeated exposure of 15 mg/kg/d, based on histopathological changes in the kidneys.


Two additional multi-generation studies were conducted after completion of the EU Risk Assessment Report 2002: Nagao (2001) and Tyl (2006). Nagao (2001) administered Nonylphenol [CAS 84852-15-3] (99%) at doses of 0, 10, 50, 250 mg/kg/d by gavage to 25 SD rats/sex/dose. Significant increases in the liver and kidney weights in males, and decreases in thymus weight in males and ovary weight in females were observed in the 50 mg/kg/d group. Histopathologic changes were found in the liver of male and female rats and kidneys of males in the 50 mg/kg group. Hence, a NOAEL of 10 mg/kg/d and a LOAEL of 50 mg/kg/d can be concluded under conditions of this study.


Tyl et al. (2006) conducted a three-generation study administering Nonylphenol [84852 -15 -3] (94.25%) to 25 SD rats/sex/dose in two different diets at dose levels of 0, 20, 200, 650, 2000ppm (approx. 0, 1.5, 15, 50, 150 mg/kg/d). The study investigates the reproductive toxicity of NP and compared ambiguous findings of two older studies with regards to specific target organ toxicity (Chapin, 1999 and Cunny 1997). The multi-generation study conducted by Chapin et al. (1999) observed kidney toxicity in F0, F1, and F2 males at 200, 650, and 2000 ppm. This contrasts the results of a 90 day study (Cunny, 1997) with the same NP concentrations and route in rats finding kidney toxicity in males only at the highest dietary concentration of 2000 ppm (~150 mg/kg/d) in F0 (2/10), F1 (4/10), and F2 (8/10). In both cases kidney lesions were medullary cysts and mineralization at the corticomedullary junction. Since Chapin et al. observed the kidney effects at the lower doses in the F0 animals (as well as the F1 and F2 males), the only clear difference (other than breeding) between the male treatments in both studies was the diet used. Cunny (1997) used Purina 5002 diet, while Chapin (1999) used NIH-07. In the Tyl (2006) study both diets were compared. Although increased absolute and relative kidney weights were observed in F1 males at 200 ppm NP (Purina 5002), they were not associated with increased incidence of the two microscopic findings (medullary cysts and mineralization at the cortico-medullary junction) and there were no renal effects (organ weights or histopathology) in F0 or F2 males at the lowest concentration (200 ppm) NP. Based on the absence of histopathological findings at this concentration a NOAEL of 200 ppm (15 mg/kg/d) was derived. At higher concentrations this study verified renal toxicity in F0, F1, and F2 adult male (650 and 2000 ppm) resulting in a LOAEL of 650 ppm (approx. 50 mg/kg/d in males).

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

In a multi-generation feeding study (Tyl 2006) increased absolute and relative kidney weights were observed in F0, F1, and F2 males at 650 ppm (appr. 50 mg/kg bw/d), associated with increased incidence of medullary cysts and mineralization at the cortico-medullary junction. The adverse effects on the kidney at low doses are male specific and do not justify a classification as toxic to specific target organ.