Essential Oil of Piper nigrum L. (Family: Piperaceae). Obtained by the steam distillation of dried unripe berries.

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Black Pepper Oil (8006-82-4) .Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 257.83mg/kg bw.When male and female Sprague-Dawley rats were exposed with Black Pepper Oil (8006-82-4) orally. Thus, comparing this value with the criteria of CLP regulation Black Pepper Oil (8006-82-4) cannot be classified as reproductive toxicant.

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Specific details on test material used for the study:

- Name of test material: Black Pepper Oil
- IUPAC name: Pepper, black, oil (Piper nigrum L.)
- Molecular formula: Unspecified
- Molecular weight: Unspecified
- Smiles : Unspecified
- Inchl: Unspecified
- Substance type: Organic
- Physical state: Liquid (colorless to slightly greenish)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: feed

Type of inhalation exposure (if applicable):

other: NOT_SPECIFIED

Vehicle:

other: 2% corn oil and basal laboratory diet

Details on exposure:

No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Main phase: males were dosed daily during premating and mating periods and up to 42 days; females were dosed up to 56 consecutive days (including a three week maturation phase, pairing, gestation and early lactation).

Frequency of treatment:

once a day, 7 days a week

Details on study schedule:

No data available

Dose / conc.:

257.83 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, plain diet

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

No data available

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

257.83 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: overall no effects on reproductive performance

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings:

not examined

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

257.83 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

mortality

Remarks on result:

other: No developmental effects was observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

(((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and "f" )  and ("g" and "h" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkene OR Allyl OR Cycloalkene by Organic Functional groups ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Allyl OR Cycloalkene OR Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Olefinic carbon [=CH- or =C<] OR Olefinic carbon [=CH2] OR Tertiary Carbon by Organic functional groups (US EPA) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Non binder, MW>500 OR Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Class 1 (narcosis or baseline toxicity) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.96

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.48

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 257.83mg/kg bw.When male and female Sprague-Dawley rats were exposed with Black Pepper Oil (8006-82-4) orally.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Black Pepper Oil (8006-82-4) .Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 257.83mg/kg bw.When male and femaleSprague-Dawleyrats were exposed with Black Pepper Oil (8006-82-4) orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

257.83 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity

In different studies, Black Pepper Oil (8006-82-4) has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for Black Pepper Oil (8006-82-4).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Black Pepper Oil (8006-82-4) .Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 257.83mg/kg bw. When male and female Sprague-Dawley rats were exposed with Black Pepper Oil (8006-82-4) orally.

It is further supported by experimental study conducted by F.J.R. Paumgartten , R.R. De-Carvalho, C.A.M. Souza, K. Madi and I.Chahoud (Braz J Med Biol Res, July 1998, Volume 31(7) 955-965 )on structurally similar read across substance β-myrcene (123-35-3).The reproductive and developmental toxicity study ofβ-myrcene (123-35-3) was performed on male and female wistar rats obtain from Bor: spf, TNO; Fa. Winkelmann, Borchen, Germany. The animals received a standard pelleted diet (Altromin 1324, Lage, Germany) and tap water ad libitum during the experiment. All rats were adapted to the conditions of our animal quarters for three weeks before starting the experiment. The test material dissolved in peanut oil and administered in dose concentration 100, 300 and 500 mg/kg body weight via oral gavage route once a day to 3 experimental group each contain 15 male and 45 female animals while the control group received a similar treatment but with vehicle only (peanut oil, 2.5 ml/kg body weight).The exposure period for male rats for 91 days prior to mating and during the mating period while for female rats for 21 days prior to mating, during the mating period, and during pregnancy and lactation until day 21 after parturition.

All the animals were observed for mortality, and signs of toxicity and weight development, Pregnant females were also observed for weight gain, signs of abortion, dystocia and prolonged duration of pregnancy. All males were sacrificed by decapitation and autopsied at the end of the mating period. All major organs were inspected macroscopically and weighed. Livers and one of the two testes were fixed in a 10% neutral buffered formalin solution for routine histological processing and light microscopic evaluation of sections stained with hematoxylin-eosin. The number of spermatozoa in the remaining testis and cauda epididymis was counted as described elsewhere (15). The following indices were used: mating index = [No. of sperm-positive females ÷ No. of mated females] x 100; pregnancy index = [No. of pregnant females ÷ No. of sperm-positive females] x 100 On day 21 of pregnancy one-third of the females in each group were anesthetized by ethyl ether inhalation and killed by decapitation. The gravid uterus was weighed with its contents. Resorption as well as living and dead fetuses were counted. The number of implantation sites was determined by the method of Salewski (16). All living fetuses were immediately weighed, numbered with a marker pen, examined for externally visible malformations and fixed in a 5% formalin solution. All fetuses were examined for skeletal anomalies after clearing with potassium hydroxide and staining with Alizarin Red S (17). All the remaining pregnant females were allowed to give birth to their offspring. From pregnancy day 20 on the dam's cages were inspected for births and the day of birth was designated as postnatal day 1. As soon as possible after birth the numbers of viable and dead new born were recorded, and the pups were sexed and weighed. Any new born death on postnatal day 1 was considered to be a stillbirth. The weight gain of the pups was recorded on postnatal days 6, 11, 16 and 21. Each pup was examined for signs of physical development and the days on which developmental landmarks appeared were recorded as follows: a) incisor eruption: the first sign of eruption through the gums of both lower incisors; b) fur development: the first detection of downy hair; c) eye opening: total separation of the upper and lower eyelids and complete opening of both eyes. At weaning (postnatal day 21) all mothers were anesthetized with ethyl ether, killed by decapitation and subjected to post mortem examination.

No signs of toxicity were apparent in male rats treated orally in dose concentration 100, 300 and 500 mg/kg body weight for 91 days prior to mating and during the mating period. There were no statistically significant differences in body weight gain between the control and the treated male and female rats during the premating (21 days) and mating periods. No deaths were induced atdoselevel 100, 300 and 500 mg/kg body weight. No other treatment-related abnormality was noted in treated rats at autopsy. Light microscopy evaluation of sections stained with hematoxylin and eosin revealed no morphological alterations in the liver or testicular tissue of male rats exposed to test material in dose level 100, 300 and 500 mg/kg body weight. The test material did not present any adverse effect on fertility indices at the dose100, 300 and 500 mg/kg body weight .The proportion of females impregnated by male rats (mating index), and the ratio of pregnant to sperm positive females (pregnancy index) did not differ between control and treated groups. Thus, no indication was found that test material administered orally at doses as high as 500 mg/kg could impair male or female fertility. Duration of pregnancy was not affected by treatment with dose level100, 300 and 500 mg/kg body weight. Also no adverse effect on labour was noted. Except for a slight increase in both absolute and relative weights of liver and kidneys of males exposed to the dose500 mg/kg body weight.

 The pup mortality in the treated groups was not above that observed in the vehicle-control group on the first day of life (stillbirths) or throughout lactation, i.e. from postnatal day 2 through day 21. The body weight of treated fetuses did not differ from that of the control group at dose level 100, 300 and 500 mg/kg body weight. The effects of prenatal exposure to test material on the occurrence of fetal skeleton abnormalities. No differences between control and treated groups were observed at doses up to 300 mg per kg body weight, but the frequency of skeletal malformations was increased at 500 mg/kg. Nonetheless, the higher incidence of skeletal abnormalities observed at this dose level seems to have been due, to a large extent, to an increase in the occurrence of anomalies such as fused os zygomatic, dislocated sternum (non-aligned sternebrae) and lumbar extra ribs, the spontaneous frequencies of which are high in our rat strain. Anyhow, the higher incidence of skeletal abnormalities as well as the embryolethal effect clearly indicated that a dose as high as 500 mg /kg is embryotoxic to rats. Hence the NOAEL was considered to be 300 mg/kg bw as no dose related effects on reproductive and developmental parameters were observed and LOAEL was considered to be 500 mg/kg bw as incidence of skeletal abnormalities as well as the embryolethal effect was observed as well as slight increase in both absolute and relative weights of liver and kidneys of males, When male and female wistar rats treated withβ-myrcene (123-35-3)by oral gavage for 91 days.

 It is further supported by experimental study conducted by T.B. Adams; C. Lucas Gavin; M.M. McGowen; W.J. Waddell; S.M. Cohen; V.J. Feron; L.J. Marnett; I.C. Munro; P.S. Portoghese; I.M.C.M. Rietjens; R.L. Smith (Food and Chemical Toxicology, 49 (2011) 2471-2494)on structurally similar read across substance D-Limonen(5989-27-5).The reproductive and developmental toxicity study ofD-Limonen(5989-27-5) was performed on pregnant Japanese White Rabbits. The test material in dose concentration 0, 250, 500 or 1000 mg/kg bw/day administered daily for 13 days (from day 6 to 18 of gestation) orally. All the animals were observed for toxicity, mortality, and weight gain and food consumption and behavioural changes.

No anomalies or behavioural changes were observed in dams of the 250 mg/kg bw/day and 500 mg/kg bw/day. Signs of maternal toxicity included increased mortality in the high-dose group(1000 mg/kg bw/day) and a significant, but temporary, decrease in body weight gain and food consumption in dose groups 500mg/kg bw/day and 1000mg/kg bw/day. No abnormalities were noted in any of the fetuses upon external examination. In addition, none of the anomalies observed upon visceral and skeletal examination were considered to be attributable to D-limonene treatment, since they were not dose dependent and were restored to normal during postnatal development. Hencethe NOAEL was considered to be 250mg/kg bw /day as no maternal toxicity was observed and LOAEL was considered to be 500 mg/kg bw as incidence of Increased maternal mortality and significant decreases in maternal body weight gain and food consumption were temporarily observed at the 500 and 1000 mg/kg bw/d dose levels was observed and The NOEL for offspring toxicity was determined to be greater than 1000 mg/kg bw/day as No treatment related effects were reported for the offspring. When pregnant Japanese White Rabbits treated with D-Limonen(5989-27-5)orally.

 Thus, based on the above studies and predictions on Black Pepper Oil (8006-82-4) and its read across substances it was considered that no adverse effects on reproductive parameter were observed. Thus, comparing this value with the criteria of CLP regulation Black Pepper Oil (8006-82-4) cannot be classified as reproductive toxicant.

 

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation Black Pepper Oil (8006-82-4) cannot be classified as reproductive toxicant.