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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
1985-06-18 to 1985-11-25
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable with restrictions because although it closely follows OECD Guideline 415, no GLP statement was provided in the study report and only data on pregnant females and pups were provided.
Justification for type of information:
In accordance with Section 1.2 of REACH Annex XI, testing does not appear to be scientifically necessary as the weight of evidence indicates no concern for reproductive (fertility and sexual function) effects from Foots oils. This is based on the lack of activity observed in several similar substances.

Foots oils are considered to be UVCB substances, and are part of the continuum of petroleum substances originating from crude oil. The substances are categorised according to their chemical specification and refining history. When considering the information available for a particular petroleum category it is appropriate to consider if other categories can provide an insight into expected toxicity. Foots oils destined for widespread/consumer use are highly refined substances, they originate from a stream of Lubricating Base Oils that act as feedstocks for most of the dewaxing operations that produce finished Foots oils. Only lubricating base oils that have been sufficiently refined i.e. they pass IP346 content ≤ 3 wt% are used to produce Foots oils. Foots oils have high paraffinic content and most of the PAHs (including 3 – 7 ring) are removed.

Concawe hypothesises that higher tier toxicological effects such as genotoxicity, repeated dose systemic toxicity, reprotoxicity (developmental and fertility) and carcinogenicity are associated with the level and types of polycyclic aromatic hydrocarbons (PAHs).
Polycyclic aromatic hydrocarbons (PAH) have a conjugated hydrocarbon ring structure and when they include other groups such as alkyl, nitro and amino groups and other elements such as nitrogen, sulphur or oxygen are known as poly cyclic aromatic compounds (PAC’s). PAH are of particular concern as historically certain PAH are considered to be associated with a number of health and environmental toxicities of which benzo[a]pyrene is the best-known example. PAH and PAC are essentially referring to the same molecules, although PAC is a more inclusive term as these contain hetero atoms (atoms other than carbon or hydrogen). However, heterocyclics are sufficiently low in petroleum products so that the two terms can be used inter-changeably. Toxicity is hypothesised to be attributed to interaction with the Aryl Hydrocarbon (Ah) receptor; further details on this hypothesis are available in Tsitou (2015), Kamelia (2019).

It is therefore predicted that Foots oils are unlikely to exhibit adverse effects in reproductive toxicity (fertility and developmental) endpoints.
Foots oils predominantly have a typical carbon range of C12 to C50, we can gain information from the component carbon pools of Foots oils from the following sources:
• Gas-to-Liquid products (GTL) which are synthetic hydrocarbons produced from natural gas using a Fisher-Tropsch process. The synthetic crude is refined to a range of products similar to those from natural crude oil but they are essentially free of unsaturated or aromatic constituents (ie PAHs) and also no sulphur-, oxygen- or nitrogen-containing constituents are present.
• Highly Refined Base Oils (which contain no PAHs and re predominantly C12 to C50)
• Lubricating base oils – these are used as feedstocks for the processes that make Foots oils but are less refined and it can be assumed they would have a worse toxicity profile. They have a typical carbon range number of C12 to C120.

References
Tsitou P, Heneweer M, Boogaard PJ. Toxicogenomics in vitro as an alternative tool for safety evaluation of petroleum substances and PAHs with regard to prenatal developmental toxicity. Toxicol in vitro 2015;29:299-307

Kamelia L, De Haan L, Ketelslegers HB, Rietjens IMCM, Boogaard PJ. In vitro prenatal developmental toxicity induced by some petroleum substances is mediated by their 3- to 7-ring PAH constituent via activation of the aryl hydrocarbon (Ah) receptor. Toxicol Lett 2019;315:64-76

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: Oily liquid
Details on test material:
- Name of test material (as cited in study report): Stock 461 (80" White Oil)
- Substance type: white mineral oil
- Physical state: liquid
- Composition of test material, percentage of components: 60% paraffins, 40% naphthenes
- Density: 0.88 g/mL

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Lakeview, New Jersey, United States
- Age at study initiation: (P) 7 wks
- Weight at study initiation: not reported
- Fasting period before study: not reported
- Housing: cages with stainless steel floors and Beta Chip Bedding for nesting material for presumed-pregnant females
- Use of restrainers for preventing ingestion (if dermal): yes, Elizabethan-style collars
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: approximately three weeks


ENVIRONMENTAL CONDITIONS: not reported

IN-LIFE DATES: From: 1985-06-18 To: 1985-11-25

Administration / exposure

Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: intact, dorsal skin
- % coverage: not reported
- Type of wrap if used: none
- Time intervals for shavings or clippings: just prior to the first test material application and weekly thereafter


REMOVAL OF TEST SUBSTANCE
- Washing (if done): excess material was removed with a gauze pad
- Time after start of exposure: 4 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): applied as mg/kg
- Concentration (if solution): not reported
- Constant volume or concentration used: not reported


VEHICLE not reported


USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: not reported
- Proof of pregnancy: female positive for sperm plug and spermatozoa were considered at day 0 of gestation
- No male replacements were made after unsuccessful mating
- Further matings after two unsuccessful attempts: not reported
- After successful mating each pregnant female was caged (how): individually
- Any other deviations from standard protocol: not reported
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data provided
Duration of treatment / exposure:
Animals were treated throughout pre-mating (approximately 10 weeks), mating (approximately 3 weeks), and post-mating (gestation days 0 through 20 for females, 9 weeks post-mating for males)
Frequency of treatment:
5 days/week except during gestation when females were treated daily
Details on study schedule:
- Age at mating of the mated animals in the study: approximately 17 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 125, 500, 2000 mg/kg/day
Basis:

No. of animals per sex per dose:
20 females per dose, 10 males per dose
Control animals:
yes
Details on study design:
no data provided
Positive control:
none

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: changes in appearance, behaviour, excretory function, ill-health, and mortality


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily; Females were observed for pathosis, abortion, premature delivery, and mortality.


BODY WEIGHT: Yes
- Time schedule for examinations: once per week during premating phase; not measured during mating phase; presumed-pregnant females were measured in days 0, 3, 6, 10, 13, 16, 18 of gestation, and days 0, 4, 7, 10, 14, and 21 post-partum (lacation).


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
Oestrous cyclicity (parental animals):
Estrous was determined in five female rats from the untreated control, vehicle control, and 2000 mg/kg-day group for two weeks prior to mating until breeding via examination of vaginal lavage fluid.
Sperm parameters (parental animals):
Data from male animals was not reported in the study.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.


PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, other: number of open eyelids for each pup was recorded on day 10 and continued daily until both eyes were open; righting reflex was examined on post-partum day 14.


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.
Postmortem examinations (parental animals):
Females were sacrificed on gestation day day 25 if they did not deliver pups or on postpartum day 21 if they did deliver pups. Thoracic and abdominal cavities were examined for gross morphologic changes. Uterus and ovaries were grossly examined and fixed in formalin. The number of implantation sites was recorded.
Postmortem examinations (offspring):
Thoracic and abdominal cavities were examined for gross morphologic changes.
Statistics:
ANOVA, group comparisons using Fisher's Exact or Dunnett's Test
Reproductive indices:
number of implantation sites
Offspring viability indices:
Live birth index, 4-day survival index, and 21-day survival index were measured.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Clinical signs in females included slight dermal irritation (erythema, flaking, scabs) at the site of application

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No signficant effects on body weight and food consumption were observed in treated females at any dose level.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No significant effect on test substance intake was observed in treated females at any dose level.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No significant effect on estrous cycle was observed in treated females at any dose level.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Sperm measures were not included in this study report.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No signficant effect on reproductive performance was observed in treated females at any dose level.

ORGAN WEIGHTS (PARENTAL ANIMALS)
No signficant effect on organ weights was observed in treated females at any dose level.

GROSS PATHOLOGY (PARENTAL ANIMALS)
No signficant effect on gross pathology was observed in treated females at any dose level.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Histopathology was not included in this study report.

OTHER FINDINGS (PARENTAL ANIMALS): none reported

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day
Sex:
female
Basis for effect level:
other: No adverse effects on reproductive parameters

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

VIABILITY (OFFSPRING)
No adverse effects were observed.

CLINICAL SIGNS (OFFSPRING)
No adverse effects were observed.

BODY WEIGHT (OFFSPRING)
No adverse effects were observed.

SEXUAL MATURATION (OFFSPRING)
No adverse effects were observed.

ORGAN WEIGHTS (OFFSPRING)
No adverse effects were observed.

GROSS PATHOLOGY (OFFSPRING)
No adverse effects were observed.

HISTOPATHOLOGY (OFFSPRING)
Histopathology results were not reported.

OTHER FINDINGS (OFFSPRING): No significant effect was observed on righting reflex or eyelid opening.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 2 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No adverse effects on reproductive parameters.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Dermal administration of white mineral oil had no adverse effects on reproductive parameters or development of pups in a one-generation study. Therefore, the NOAEL is greater than or equal to 2000 mg/kg/day for both the parental and F1 generation.
Executive summary:

In a one-generation reproduction study, white mineral oil was administered dermally to Sprague-Dawley rats (10/dose for males, 20/dose for females) at dose levels of 0, 125, 500, or 2000 mg/kg bw/day at a frequency of 5 days/week during premating and daily during gestation (for females).

 

No mortality was observed in any treatment groups. No treatment-related changes in body weight gain or food consumption were observed in the females of the parental generation. No adverse effects were noted in the number of implantation sites per dam, litter size, or length of gestation in treated animals. Treatment-related clinical signs included erythema, scabs, and flaking at application site at all dose levels. No signs of gross toxicity were observed at necropsy. The parental systemic NOAEL is greater than or equal to 2000 mg/kg bw/day for females. Data on males were not provided in this study report.

 

The offspring exhibited no significant differences in body weight gain, eyelid disjunction, righting reflex, or viability in treated groups versus control.  No treatment-related signs of gross pathology were noted at necropsy. The offspring NOAEL is greater than or equal to 2000 mg/kg bw/day.

 

This study received a Klimisch score of 2 and is classified as reliable with restrictions because, although it closely follows OECD Guideline 415, no GLP statement was provided in the study report and only data on pregnant females and pups were provided.