Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1985-01-22 to 1987-02-06
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was classified as reliable with restriction because it generally followed OECD 414; however, some deviations were noted.
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 developmental toxicity effects from paraffin wax. This is based on the lack of activity observed in several similar substances, an assessment made by another regulatory authority (EFSA), and an assessment by recognised experts (American College of Toxicology).

Parraffin wax is considered to be a UVCB substance, and is 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. Paraffin waxes 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 paraffin and microcrystalline waxes. Only lubricating base oils that have been sufficiently refined i.e. they pass IP346 content ≤ 3 wt% are used to produce paraffin waxes. Paraffin waxes 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 paraffin and hydrocarbon waxes are unlikely to exhibit adverse effects in reproductive toxicity (fertility and developmental) endpoints.
Paraffin waxes predominantly have a typical carbon range of C12 to C85, we can gain information from the component carbon pools of paraffin waxes 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 paraffin wax 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 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Only one dose level examined; dose (5000 mg/kg) exceeded the limit dose (1000 mg/kg)
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 oils
- Lot/batch No.: CRU #85081
- Density: 0.88 g/mL

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Lakeview, NJ
- Age at study initiation: Males: 79 days old; Females: 58-65 days old
- Diet (e.g. ad libitum): Purina Certified Rodent Chow #5002; ad libitum
- Water (e.g. ad libitum):Ad libitum
- Acclimation period: Three weeks

IN-LIFE DATES: From: 1985-01-22 To: 1985-03-15

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
Animals were dosed once daily via gavage during gestation days 6 through 19. Dosing volume was adjusted daily based on individual animal body weight, dose level, and density of the test material.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
One male and one female were co-housed during mating. Females were examined daily for the presence of in situ vaginal sperm plug. Vaginal lavage fluid was examnied for spermatoza in those who exhibited an in situ vaginal sperm plug. Females exhibiting both an in situ vaginal sperm plug and speratoza in the vaginal fluid were considered to be at day 0 gestation. Cohabitation continued until 122 presumed-pregnant females were obtained.
Duration of treatment / exposure:
Gestation days 6 through 19
Frequency of treatment:
Once daily
Duration of test:
Acclimatization: 22 January, 1985 through Cesarean Sectioning 15 March, 1985
Doses / concentrations
Remarks:
Doses / Concentrations:
5000 mg/kg
Basis:
nominal conc.
No. of animals per sex per dose:
20
Control animals:
yes
Details on study design:
Controls were administered tap water

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily for pathosis, abortion, premature delivery, and death

BODY WEIGHT: Yes
- Time schedule for examinations: 0, 6, 8, 10, 13, 16, 18, and 20

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 19 via carbon dioxide
- Organs examined: All organs grossly examined; thoracic and abdominal cavities

OTHER: Clinical chemistry (see Table 1)
Ovaries and uterine content:
Uterus and ovaries were excised and grossly examined. For pregnant females, the number of corpora lutea were counted and recorded. The number and location of implantations; early, mid, and late resorptions; and live and dead foetuses were recorded. Ovaries were grossly examined and discarded and the uterus was microscopically examined in non-pregnant females.
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter
- Head examinations: No data
Statistics:
Maternal biophase, cesarean section data, and foetal data were analyzed by analysis of variance followed by groups comparisons using Fisher's Exact or Dunnett's Test. All experimental data (inhalation and oral groups) were compared against dermal group data. Differences were considered statistically significant if the probability of the difference being due to chance was less than 5%.
Indices:
Female mortality; male foetal viability; female foetal viability; preimplantation loss; resportions
Historical control data:
No data reported.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 5 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 5 000 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Remarks on result:
other: see Details on embyotoxic/teratogenic effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No adverse effects were noted on reproductive parameters or on the in utero suvival or development of the offspring. The developmental NOAELs are greater than or equal to the highest dose tested via gavage.
Executive summary:

In a developmental toxicity study, Stock 461 was administered to 20 female Sprague-Dawley rats/dose via gavage at dose levels of 0 or 5000 mg/kg bw/day from days 6 through 19 of gestation.

 

There was no maternal toxicity observed at 5000 mg/kg/day. Consequently, the maternal NOAEL is greater than or equal to 5000 mg/kg/day.

 

There was no developmental toxicity observed at 5000 mg/kg/day. Consequently, the developmental NOAEL is greater than or equal to 5000 mg/kg/day.

 

This study received a Klimisch score of 2 and is classified as reliable with restriction because it generally followed OECD 414; however, some deviations were noted.