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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

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Diss Factsheets

Administrative data

endocrine system modulation
Type of information:
other: review
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
review of data from valid QSAR models (falling into their applicability domain, with adequate documentation) and from experimental GLP studies

Data source

Reference Type:
Appraisal of the human health related toxicological information available on dicyclopentadiene (DCPD) in view of assessing the substance's potential to cause endocrine disruption.
Tencalla, F., Kocabas, N.A., Rooseboom, M., Rushton, E., Synhaeve, N. and Petry, T.
Bibliographic source:
Regulatory Toxicology and Pharmacology 126 (2021): p 105040

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
The publication evaluates toxicological and mechanistic information in order to establish or exclude endocrine disruption (ED)-related mechanism of DCPD in developmental effects.
GLP compliance:
Type of method:
other: review
Endpoint addressed:
developmental toxicity / teratogenicity
other: endocrine disruption

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
Name of substance: Dicyclopentadiene (3a,4,7,7a-tetrahydro-4,7-methanoindene)
EC No. 201-052-9
CAS No. 77-73-6
Specific details on test material used for the study:
Name of substance: Dicyclopentadiene (3a,4,7,7a-tetrahydro-4,7-methanoindene)
EC No. 201-052-9
CAS No. 77-73-6

Test animals

other: n/a
Details on test animals or test system and environmental conditions:

Administration / exposure

Route of administration:
other: n/a
Details on exposure:
Details on analytical verification of doses or concentrations:
Duration of treatment / exposure:
Frequency of treatment:
Post exposure period:
No. of animals per sex per dose:
Details on study design:
In silico, in vitro and in vivo data regarding ED mechanisms was evaluated from the following sources:
• Literature review (July 2019 - September 2020)
• (Q)SAR modelling (all tools are recommended in the ECHA guidance for the identification of endocrine disruptors in the context of Regulations (EU) No. 528/2012 and (EC) No. 1107/2009 (2018)):
-OECD (Q)SAR Toolbox v.4.4.1 software (OECD, 2020)
-Derek Nexus v. 6.0.1 (Barber et al., 2015)
-Endocrine Disruptome (Kolsek et al., 2014)
-Danish (Q)SAR database (DTU Food, 2020)
-VEGA platform (Benfenati et al., 2013)
-US EPA ToxCast models (Williams et al., 2017)
• Information from US EPA’s Toxicity Forecaster (ToxCast) database
• Studies submitted for regulatory purposes


Positive control:

Results and discussion

Details on results:

Any other information on results incl. tables

Literature review:

Literature search did not yield any relevant studies for DCPD endocrine assessment.

OECD (Q)SAR toolbox:

The OECD QSAR toolbox was used to screen for functional groups and structural alerts for reproductive and developmental toxicity with a focus on the following: estrogen receptor binding, rainbow trout estrogen receptor (rtER) Expert system USEPA, retinoic acid receptor binding and developmental and reproductive toxicity (DART) scheme. The QSAR toolbox showed that DCPD does not bind to estrogen or retinoic acid receptors, it was also predicted to be negative for DART (Table 1). A structural alert was identified for rtER Expert System USEPA, however, it was not considered to be relevant since DCPD does not fulfil the criterion of similarity with tamoxifen as the Tanimoto coefficient is very low (0.02).

Table 1 OECD (Q)SAR Toolbox v. 4.4 screen of DCPD

 Profiler Information  Result 
 Estrogen Receptor Binding (v. 2.2)

Method relevant for reproductive toxicity endpoints in fish and mammals

Non-binder, without OH or NH2 group

 Rainbow trout Estrogen Receptor (rtER) Expert System USEPA (v. 1.0)

Identifies potential to bind rainbow trout estrogen receptor by using criteria covered by the US EPA estrogen Expert System


Multicyclic hydrocarbons

 Retinoic Acid Receptor Binding (v 1.1)

Method relevant for developmental toxicity; identifies potential to bind retinoic acid receptor

Not possible to classify

according to these rules*

 DART scheme (v.1.3)

Decision tree to identify chemicals with structural features associated with DART toxicants

Not known precedent reproductive and

developmental toxic potential

*The substance does not match the structural criteria specified in the boundaries of the profiler.

Derek Nexus:

Derek Nexus did not identify any structural alerts for any of the tested profilers: androgen receptor (AR) modulation, developmental toxicity, glucocorticoid receptor antagonism, ER modulation, estrogenicity, teratogenicity as well as adrenal gland testicular and thyroid toxicity.

Endocrine disruptome:

Endocrine disruptome is used to predict docking to 18 structures of nuclear receptors including AR, ER (alpha and beta), glucocorticoid receptor (GR), mineralcorticoid receptor, liver X receptors (LXR; alpha and beta), peroxisome proliferator activated receptors (PPAR; alpha, beta and gamma), progesterone receptor (PR), retinoid X receptor (RXR; alpha) and thyroid receptors (TR; alpha and beta). DCPD showed medium probability of binding to AR as antagonist, however, the antagonism model did not present a high 'AUC' value suggesting lower performance, and low probability of binding to all other human nuclear receptors.

Danish (Q)SAR database:

Danish (Q)SAR database is used to predict ER alpha binding and activation, AR antagonism, thyroperoxidase (TPO) inibition, TR binding, arylhydrocarbon receptor (AhR) activation, pregnane X receptor (PXR) binding and CYP3A4 induction. A battery approach was used to reduce the 'noise' from individual models to improve accuracy and/or broaden applicability domain. DCPD was predicted to have very low binding affinity for TR alpha and beta (human) and not bind or activate/inhibit the remaining receptors or induce CYP3A4 (Table 2).

Table 2 Summary of the predictions of the Danish (Q)SAR database for DCPD

Model predictions Result
Estrogen receptor a binding, full training set (Human in vitro) NEG_IN; NEG (Experimental)
Estrogen receptor a binding, balanced training set (Human in vitro) NEG_IN; NEG (Experimental)
Estrogen receptor a activation (Human in vitro) NEG_IN; NEG (Experimental)
Androgen receptor antagonism (Human in vitro) NEG_IN
Thyroperoxidase (TPO) inhibition (Q)SAR1 (Rat in vitro) NEG_OUT (Leadscope)
Thyroperoxidase (TPO) inhibition (Q)SAR2 (Rat in vitro) NEG_IN (Leadscope); NEG (Exp)
Thyroid receptor a binding (Human in vitro); µM 10602.25 IN
Thyroid receptor ß binding (Human in vitro); µM 21210.87 IN
Arylhydrocarbon (AhR) Activation – Rational final model (Human in vitro) INC_OUT (Leadscope)
Arylhydrocarbon (AhR) Activation – Random final model (Human in vitro) INC_OUT (Leadscope)
Pregnane X Receptor (PXR) Binding (Human in vitro) NEG_IN
Pregnane X Receptor (PXR) Binding (Human in vitro) NEW NEG_IN (Leadscope)
Pregnane X Receptor (PXR) Activation (Human in vitro) NEG_IN (Leadscope)
Pregnane X Receptor (PXR) Activation (Rat in vitro) NEG_IN (Leadscope)
CYP3A4 Induction (Human in vitro) NEG_IN (Leadscope)

NEG: negative; IN: inside applicability domain; OUT: outside applicability domain; Exp: result of experimental data included in the training set.


VEGA is used to predict ER binding using two models: Estrogen Recptor Binding Affinity model (IRFMN) 1.0.1. and Estrogen Receptor-Mediated Effects (IRFMN/CERAPP) 1.0.0. Both models predicted that DCPD does not bind to ER or induce ER-mediated effects. The predictions were also supported by experimental data in the training set.

Results from the US EPA ToxCast high-throughput screening (HTS):

DCPD was tested in 610 ToxCast assays (46 were ED- specific, 47 were associated with endocrine-related nuclear receptors or pathways that may impact reproductive/development parameters). DCPD was inactive in all, except for Novascreen NVS_NR_hPPARg, assays. The NVS_NR_hPPARg assay measures the modulation of PPARg activity relative to a known receptor antagonist. Activation of PPARg is associated with the impairment of steroidogenesis leading to reproductive toxicity in rodents. Activation of this receptor is not mediated by the estrogen receptor nor is it linked to direct aromatase inhibition and the key events in the pathway comprise the activation of PPAR¿, followed by the disruption of hormonal balance which leads to irregularities of the ovarian cycle which may be the cause of impaired fertility. However, this is not seen with DCPD exposure. DCPD was active in the assay with an AC50 value of 2.65 µM, which is 10 -fold and 1000 -fold less potent that the standard assay antaginist Fluazinam and other substances with the highest activity, respectively. In addition, DCPD was also inactive in 15 -cell based PPAR assays in ToxCast which target receptor transactivation or protein stabilisation in the signalling pathway which suggests that DCPD binding to PPARg does not resutl in activation of the receptor. Lastly, the US EPA considers a chemical to be active in a pathway the chemical should be active in at least five assays mapping the same pathway. Therefore, DCPD was considered inactive for both PPAR/PPARg and the EATS-related ED pathways.

Table 3 Summary of the predictions obtained by the US EPA ToxCast models for DCPD

Model Receptor Agonist Antagonist Binding
ToxCast Pathway Model (AUC) Androgen  0 0 -
ToxCast Pathway Model (AUC) Estrogen 0 0 -
COMPARA (consensus) Androgen  Inactive Inactive Inactive
CERAPP Potency Level (from literature) Estrogen - Inactive -
CERAPP Potency Level (consensus) Estrogen Inactive Inactive Inactive

AUC scores =0.1 = positive; 0 > AUC <0.1 = inconclusive; <0.001 (truncated up as 0) = negative.

Table 4 Results of EDSP-21 high throughput screening in vitro results of relevance for DCPD

Modality ID Assay* Effect direction Effect type Results
Estrogen 1 OT_ER_ERaERa_0480 Gain Receptor dimerization Inactive
  2 OT_ER_ERaERa_1440 Gain Receptor dimerization Inactive
  3 OT_ER_ERbERb_0480 Gain Receptor dimerization Inactive
  4 OT_ER_ERbERb_1440 Gain Receptor dimerization Inactive
  5 OT_ER_ERaERb_0480 Gain Receptor dimerization Inactive
  6 OT_ER_ERaERb_1440 Gain Receptor dimerization Inactive
  7 ATG_ERE_CIS_up Gain Receptor (trans)activation Inactive
  8 ATG_ERa_TRANS_up Gain Receptor (trans)activation Inactive
  9 TOX21_ERa_BLA_Agonist_ratio Gain Receptor (trans)activation Inactive
  10 TOX21_ERa_LUC_VM7_Agonist Gain Receptor (trans)activation Inactive
  11 OT_ERa_EREGFP_0120 Gain Protein induction/gene expression  Inactive
  12 OT_ERa_EREGFP_0480 Gain Protein induction/gene expression Inactive
  13 ACEA_ER_80hr Gain Cell proliferation Inactive
  14 NVS_NR_bER Loss Receptor binding Inactive
  15 NVS_NR_mER Loss Receptor binding Inactive
  16 NVS_NR_hER Loss Receptor binding Inactive
  17 TOX21_ERa_BLA_Antagonist_ratio Loss Receptor (trans)activation Inactive
Androgen 18 UPITT_HCI_U2OS_AR_TIF2_Nucleoli_Agonist Gain Receptor binding Inactive
  19 OT_AR_ARSRC1_0480 Gain Cofactor Recruitment Inactive
  20 OT_AR_ARSRC1_0960 Gain Cofactor Recruitment Inactive
  21 ATG_AR_TRANS_up Gain Receptor (trans)activation Inactive
  22 TOX21_AR_BLA_Agonist_ratio Gain Receptor (trans)activation Inactive
  23 TOX21_AR_LUC_MDAKB2_Agonist Gain Receptor (trans)activation Inactive
  24 OT_AR_ARELUC_AG_1440 Gain Protein induction/gene expression Inactive Inactive
  25 UPITT_HCI_U2OS_AR_TIF2_Nucleoli_Antagonist Loss Receptor binding Inactive
  26 TOX21_AR_BLA_Antagonist_ratio Loss Receptor (trans)activation Inactive
  27 TOX21_AR_LUC_MDAKB2_Antagonist_0.5 nM_R1881 Loss Receptor (trans)activation Inactive
Thyroid 28 ATG_THRa1_TRANS_up Gain Receptor (trans)activation Inactive
  29 TOX21_TSHR_Agonist_ratio Gain Receptor (trans)activation Inactive
  30 TOX21_TSHR_Antagonist_ratio Loss Receptor (trans)activation Inactive
  31 TOX21_TR_LUC_GH3_Agonist Gain Receptor (trans)activation Inactive
  32 TOX21_TR_LUC_GH3_Antagonist Loss Receptor (trans)activation Inactive
  33 ATG_THRa1_TRANS_dn Loss Receptor (trans)activation Inactive
  34 NVS_GPCR_rTRH Loss Receptor (trans)activation Inactive
Steroido-genesis 35 TOX21_Aromatase_ Inhibition Loss Aromatase activity Inactive

* All 11 viability/specificity assays not presented in the table were also found to be inactive.

Regulatory in vivo assays (described in the dossier sections 7.5.1 and 7.5.2):
No studies related to the selected ED mechanisms (e.g. OECD 440 or 441) were identified.

Oral repeated dose studies:

Oral repeated dose study in rats (OECD 422; Maatsura 1993) showed no adverse effects up to concentrations of 20 mg/kg/day. Two females died prior to scheduled necropsy and the remaining animals in the group showed decreased food consumption as well as body weight gain in the 100 mg/kg/day dose group (highest dose tested). In the same dose group, male animals showed tubular epithelium of the kidney and an increase in fatty droplet in the fascicular zone of the adrenals was observed in both sexes. In the 20 mgk/kg/day dose group, similar findings were observed in kidneys and adrenals.The NOAEL for systemic toxicity was concluded to be 20 mg/kg/day for females and 4 mg/kg/day for males.

In a 90 -day oral toxicity study in dogs (similar to OECD 409; Litton Bionetics 1980), no mortalities occured in any dose groups and there were no significant clinical differences between control and treatment groups except for slightly higher frequency of soft stools and vomiting in the treatment group. Therefore, it was concluded that DCPD causes no significant toxicity in dogs and the NOAEL was considered to b 28.2 mg/kg/day for males and 28.8 mg/kg/day for females.

Inhalation repeated dose studies:

Inhalation repeated dose study in mice (similar to OECD 413; Kransler 2014) showed that 20% of animals died when exposed to 276 mg/m3 (equivalent to 8163 mg/kg/day; highest dose tested) DCPD due to pulmonary congestion and potential kidney failure. In the lower exposure concentrations, no more than two animals per dose died. Animals in the 27.6 or 276 mg/m3 (equivalent to 8163 and 816 mg/kg/day) dose groups showed loss of coordination and/or decreased activity during exposure to DCPD and females showed a decrease in serum albumin indicating slight liver dysfunction. In addition, female absolute and relative liver weights were increased in these dose groups, however, no histopathological changes were observed. Therefore, the NOAEC was concluded to be 27.6 mg/m3 (equivalent to 816 mg/kg/day).

In a 13 -week inhalation study in rats (Bevan et al. 1982), no mortality, clinical effects, haematological or blood chemistry changes were observed in response to exposure up to 50 ppm (equivalent to 5202 mg/kg/bw/day). In the highest dose group, relative liver weights were increased as well as alterations in renal function, sodium and potassium excretion rates and increased urine volume were observed in males, however, they returned to normal during the recovery period. In addition, hyaline droplet accumulation, nephritis and glomelural basment thickening were also observed in male kidneys of these dose groups with only hyaline droplets returning to noral during recovery. However, these observations were consistent with male rat-specific glomerulonephopathy. Therefore, it was concluded that 50 ppm (equivalent to 5202 mg/kg/day) DCPD results in low systemic toxicity.

In a supporting inhalation study in rats (Kinkead et al. 1972), one animal in 73.8 ppm (equivalent to 8810 mg/kg/day; highest dose tested) and in 19.7 ppm (equivalent to 2363 mg/kg/day) dose groups displayed convulsions for five minutes after exposure on two days of dosing. In addition, liver and kidney absolute as well as relative weights were significantly increased at all doses in male animals. Additionally, males in the 19.7 ppm and 35.2 ppm (equivalent to 8810 and 4195 mg/kg/day) dose groups showed kidney effects.

Lastly, an inhalation study in dogs (Kinkead et al. 1971) showed dose-dependent increases in absolute kidney and liver weights, however, no histopathological changes were observed.

Developmental and reproductive toxicity (DART) studies:

In a DART study (combined repeated dose toxicity and reproduction/developmntal toxicity screen study similar to OECD 422; Matsuura 1993) in rats, decreased body weight gain and food consumption were observed in the 100 mg/kg/day dose group (the highest dose tested). Two females in the 100 mg/kg/day group did not nurse their litters resulting in total litter loss. In addition, low neonate viability index as well as lower birth weight and weight gain were observed in the 100 mg/kg/day dose group, likely due to maternal toxicity. However, no effects on mating, fertility, gestation, delivery or parturition were observed. The maternal and developmental NOAELs were considered to be 20 mg/kg/day , while the NOAEL for reproductive/developmental effects in parental males was 100 mg/kg/day.

In another study (Litton Bionetics 1978), rats orally dosed with DCPD showed clinical signs and body weight changes, however, no other effects on maternal animals or foetuses were observed at any dose up to 60 mg/kg/day, which was considered to be the maternal and developmental toxicity NOAEL.

In a separate dose range finding study in rats (Environmental Health Research and Testing Inc. 1993), lethal maternal toxicity occurred in 300, 400 and 500 mg/kg/day (highest dose tested) groups and a one death occurred in the 200 mg/kg/day group. Additionally, decrease in body weight gain was observed in the 50 and 200 mg/kg/day dose groups. The avergare foetal weight was also slightly lower in the 200 mg/kg/day dose group. It was concluded that DCPD causes maternal toxicity at 200 mg/kg/day doses.

In a dose range finding study in rabbits (Environmental Health Research and Testing Inc. 1993), systemic and lethal toxicity were observed in the 300 and 400 mg/kg/day (highest dose tested) groups. Only maternal body weight gain decrease was osberved in the 200 mg/kg/day, and abortion of one litter occurred in the 100 mg/kg/day. It was concluded that the maternanl NOAEL was 25 mg/kg/day while the developmental toxicity NOAEL was 300 mg/kg/day.

A three-generation reproductive study in rats (Litton Bionetics 1978) found no adverse effects on the general condition of the animals across the three generations. 750 ppm (4.06 mg/L; highest dose administered) caused systemic and reproductive toxicity, food consumption was reduced in F1 generation in a dose-related manner with statistical significance in the 750 ppm dose group and pup weight was reduced in the F3 generation. Therefore, the NOAEL was considered to be 80 ppm (69 ppm actual concentration).

Lastly, in an NTP continuous breeding study rats (Jamieson et al. 1995) were orally dosed with DCPD and F1 generation males showed increased liver and kidney weights at 10, 30 and 100 mg/kg/day (highest dose administered) groups with no mention of systemic toxicity in females. Reduction in pup body weights, increased pup mortality and reduced pup survival were observed in the 100 mg/kg/day F1 generation and the effects in the F2 generation were not greater, however, it is unclear whether the pup weight reductions in F1 and F2 generations were secondary to maternal toxicity. It was concluded that DCPD is not selective reproductive toxicant as liver and kidney efects were observed at and below reproductive toxicity effects.

Applicant's summary and conclusion

There is no evidence of endocrine activity of DCPD that would lead to developmental toxicity.
Executive summary:

This publication reviewed data from QSAR-based predictions, US EPA ToxCast HTS assays as well as in vivo repeated dose, reproductive and developmental toxicity studies. No in vivo assays investigating selected endocrine mechanisms or pathways were identified. The QSAR predictions found no potential for DCPD to bind to estrogen, androgen, thyroid or steroidgenesis receptors. This was also confirmed by the lack of DCPD activity in endocrine disruption relevant ToxCast HTS assays which have been associated with enodrine, androgen, thyroid and steroidogenesis (EATS)-mediated endocrine activity. In vivo studies showed little system toxicity associated with repeated exposure to DCPD. Liver and kidney changes were mild and did not trigger specific target organ toxicity (STOT RE) classicifaction under EU CLP. Thymus, adrenals, testes or epididymis absolute and relative weights or histopathological findings were affected by DCPD exposure. The developmental and reproductive toxicity (DART) studies showed no evidence of endocrine mediated mode of action of the observed foetotoxicity. An increase in fatty droplets in the fascicular zone of the adrenals in both males and females in the high dose and in males in the mid dose group was observed in an OECD 422 study, however, this does not provide evidence for endocrine disruption related effects.

Therefore it was concluded that neither QSAR data, in vitro mechanistic nor in vivo studies show evidence of endocrine activity of DCPD that would lead to developmental effects.